Rosacea

Complex MONDO:0006604 Pathograph 45 Show in embeddings browser Dermatological Disease Inflammatory Skin Disease

Rosacea is a chronic relapsing inflammatory facial dermatosis centered on persistent or episodic centrofacial erythema, flushing, telangiectasia, and papulopustular lesions, with phymatous and ocular involvement in a subset of patients. Current mechanistic models emphasize dysregulated innate immunity, neurovascular hyperreactivity, skin barrier impairment, and trigger-dependent disease amplification.

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Subtypes

Erythematotelangiectatic Rosacea

Predominantly vascular rosacea phenotype characterized by persistent centrofacial erythema, flushing, and telangiectasia without dominant papulopustular or phymatous change.

Show evidence (2 references)

PMID:28150107 SUPPORT Human Clinical

"Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"

This review explicitly recognizes erythematotelangiectatic rosacea as one of the four canonical clinical subtypes.

PMID:27718519 SUPPORT Human Clinical

"The following two features were independently considered diagnostic for rosacea: (i) persistent, centrofacial erythema associated with periodic intensification; and (ii) phymatous changes."

This phenotype-led consensus supports the core vascular features that anchor erythematotelangiectatic rosacea.

Papulopustular Rosacea

Inflammatory rosacea subtype with persistent facial erythema accompanied by papules and pustules in the central face.

Show evidence (2 references)

PMID:28150107 SUPPORT Human Clinical

"Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"

This review explicitly recognizes papulopustular rosacea as a major clinical subtype.

PMID:28150107 SUPPORT Human Clinical

"Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."

This supports the inflammatory papule-pustule phenotype that defines papulopustular rosacea.

Phymatous Rosacea

Tissue-remodeling subtype marked by thickening and hypertrophy of facial skin and sebaceous structures, most commonly affecting the nose as rhinophyma.

Show evidence (2 references)

PMID:28150107 SUPPORT Human Clinical

"Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"

This review explicitly recognizes phymatous rosacea as one of the canonical clinical subtypes.

PMID:41918801 SUPPORT Human Clinical

"Phymatous rosacea (PhR), also known as "rhinophyma", refers to a benign condition characterized by the excessive proliferation of sebaceous glands and fibrosis in the facial skin due to rosacea"

This supports the hypertrophic and fibrotic tissue-remodeling pattern characteristic of phymatous rosacea.

Ocular Rosacea

Ocular subtype involving chronic inflammatory disease of the eyelids and ocular surface, often with blepharitis, meibomian dysfunction, dryness, and photophobia.

Show evidence (2 references)

PMID:28150107 SUPPORT Human Clinical

"Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"

This review explicitly recognizes ocular rosacea as a canonical rosacea subtype.

PMID:40522449 SUPPORT Human Clinical

"Ocular rosacea is a chronic inflammatory disease that affects the surface of the eye and the eyelids."

This supports ocular rosacea as a distinct subtype centered on eyelid and ocular surface inflammation.

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Mechanistic Hypotheses

Lipid-metabolic reprogramming centred on ACSL5 accompanies, and may promote, macrophage infiltration in erythematotelangiectatic rosacea

etr_lipid_metabolism_acsl5_macrophage EMERGING Erythematotelangiectatic Rosacea

Evidence balance 2 support

Transcriptomic profiling of ETR skin (GEO GSE65914, 14 ETR versus 20 control biopsies) enriches for lipid-metabolism and PPAR-signaling genes, with ACSL5 and ACADVL nominated as hub genes, and ACSL5 co-localizes with M1 macrophage markers in a rosacea mouse model. The hypothesis is that fatty-acid metabolic reprogramming in lesional skin is upstream of macrophage-driven inflammation in the vascular subtype, rather than a bystander of it. It rests on a single WGCNA study plus co-localization, so the ACSL5 pathophysiology node carries mechanism_confidence PROVISIONAL. A confirmatory re-analysis of GSE65914 asks whether the lipid-metabolism signature and the ACSL5/ACADVL hub genes reproduce in ETR under a prespecified contrast, and whether they track macrophage marker expression (CD68, CD163, CD86) within the same samples. Downstream causal edges that belong to this hypothesis opt in via hypothesis_groups: [etr_lipid_metabolism_acsl5_macrophage].

Confirmatory dataset run on geo:GSE65914 (kb/hypotheses/Rosacea/etr_lipid_metabolism_acsl5_macrophage/, assessed PARTIALLY_SUPPORTED): ACSL5 (5.6x), PPARG (4.5x) and ACADVL (2.0x) are strongly higher in ETR with CPT1A unchanged, and CD68, CD163 and CD86 are all higher (1.4-1.8x), robust to collapsing the two replicate arrays per subject. Within ETR, ACSL5 does not correlate with any macrophage marker (all q > 0.45), and the CD86/CD163 balance shifts toward the M2 marker CD163 with the M2 regulator PPARG up. The label was accordingly reworded from "drives M1 macrophage infiltration" to the co-occurrence the data support; a driver role and M1 polarization remain untested. The original study derived its signature from the same series, so this reproduces the analysis, not the cohort; independent replication would need a second ETR transcriptome, which does not yet exist in a public repository.

Pathograph links

ACSL5-Mediated Lipid Metabolism Dysregulation -> Immune cell infiltration INDIRECT KNOWN INTERMEDIATES In a rosacea mouse model, ACSL5 upregulation co-localizes with increased M1 macrophage infiltration, suggesting a mechanistic link between lipid-metabolic dysregulation and macrophage-driven inflammation, though the finding is correlative (co-localization) rather than a demonstrated causal perturbation. Intermediates: lipid metabolic reprogramming; M1 macrophage polarization

Deep research

OpenScientist citations 3 citations 2026-09-06T18:23:58.390069

Show evidence (2 references)

PMID:40195491 SUPPORT Human Clinical

"we identified 304 differentially expressed genes in erythrotelangiectasia rosacea (ETR), primarily enriched in lipid metabolism pathways. Support vector machine (SVM), linear regression analyses and network analysis revealed ACADVL and ACSL5 as potential therapeutic targets."

The originating transcriptomic observation.

PMID:40195491 SUPPORT INDIRECT Model Organism

"Immunofluorescence validation confirmed significant ACSL5 upregulation and increased M1 macrophage infiltration in the rosacea mouse model. The co-localization of ACSL5 with M1 macrophage markers suggests a mechanistic link between lipid metabolism and inflammatory responses."

The co-localization on which the causal reading rests; correlative, hence the hypothesis rather than an established mechanism.

LL-37 drives papulopustular lesions through NLRP3 inflammasome activation and IL-1beta maturation

ll37_nlrp3_il1b_papulopustular EMERGING Papulopustular Rosacea

Evidence balance 2 support

The cathelicidin fragment LL-37 is a recognized activator of the NLRP3 inflammasome, rosacea skin over-expresses NALP-3 (NLRP3) and CASP1 together with IL1B most strongly in papulopustular disease, and the LL-37-induced inflammatory infiltrate in mice is reported to be NLRP3-dependent. The hypothesis places inflammasome-processed IL-1beta as the route from cathelicidin signaling to the neutrophilic papule and pustule, distinct from the mast-cell and Th1/Th17 arms of the same LL-37 signal. In this entry it is supported by expression associations and a review synthesis, not by a human perturbation. A confirmatory re-analysis of the paired lesional versus non-lesional papulopustular explant RNA-seq (GEO GSE155141), which independently implicated IL-1beta, asks whether NLRP3, CASP1, PYCARD, IL1B and IL18 are coordinately elevated in lesional skin and further induced by IL-1beta treatment of non-lesional explants. Downstream causal edges that belong to this hypothesis opt in via hypothesis_groups: [ll37_nlrp3_il1b_papulopustular].

Confirmatory dataset run on geo:GSE155141 (15 samples: paired non-lesional and lesional PPR explants, plus IL-1beta-treated non-lesional explants; kb/hypotheses/Rosacea/ll37_nlrp3_il1b_papulopustular/, assessed PARTIALLY_SUPPORTED): IL-1beta raised NLRP3 mRNA (paired p = 0.025, dz = 1.57, BH q = 0.196) with IL1B and IL1RN trending up, consistent with transcriptional priming of the sensor; the lesional versus non-lesional contrast was null for all eight genes and CAMP/KLK5 were flat, so the post-translational assembly and maturation steps that define the hypothesis remain untested at the transcript level. The mouse loss-of-function evidence (PMID:33745908) was promoted onto the LL-37 to NLRP3 edge as a result of the run's post-lock literature check.

Pathograph links

LL-37 generation -> NLRP3 Inflammasome Activation DIRECT LL-37 activates the NLRP3 inflammasome, among other downstream pathways, driving pro-inflammatory cytokine production; in mice the LL-37-induced inflammatory infiltrate is NLRP3-dependent.

NLRP3 Inflammasome Activation -> Papulopustular inflammation INDIRECT KNOWN INTERMEDIATES Inflammasome-processed IL-1beta contributes to the neutrophilic inflammatory lesion; inflammasome gene expression is highest in the papulopustular subtype. Intermediates: IL-1beta maturation and release; neutrophil recruitment

Deep research

OpenScientist citations 2 citations 2026-09-06T18:18:27.635584

Show evidence (2 references)

PMID:23171449 SUPPORT Human Clinical

"Skin sample analysis showed a higher expression of genes encoding pro-inflammatory cytokines (Il-8, Il-1b, TNF-a) and inflammasome-related genes (NALP-3 and CASP-1) in rosacea, especially PPR."

Human lesional expression of the inflammasome components, enriched in the papulopustular subtype.

PMID:42325915 SUPPORT Human Clinical

"LL-37 subsequently activates multiple downstream pathways, including NF-κB, the NLRP3 inflammasome, and JAK/STAT, leading to the production of pro-inflammatory cytokines."

Review synthesis placing NLRP3 downstream of LL-37.

Rosacea GWAS susceptibility loci act through altered expression in lesional skin, including a TLR1-TLR2 heterodimer axis

gwas_loci_lesional_expression EMERGING

Evidence balance 2 support

The genome-wide significant rosacea loci fall into two groups: immune (HLA-DRA/BTNL2, the HLA class II alleles, IL13, IRF1, TLR1) and pigmentation (IRF4, HERC2-OCA2, SLC45A2). The hypothesis is that the immune loci are expressed and differentially regulated in lesional skin, so that germline susceptibility acts through the innate and adaptive inflammatory program modelled in this entry rather than only through skin phototype. Aponte et al. found three loci (PSMB9-HLA-DMB, HERC2-OCA2, NRXN3-DIO2) differentially expressed in lesional versus non-lesional skin, and Chang et al. localized HLA-DRA and BTNL2 protein to the perifollicular infiltrate, but the newer Million Veteran Program loci, TLR1 in particular, have never been tested this way. TLR1 is the obligate heterodimer partner of TLR2 for triacylated lipopeptide sensing, so a TLR1 risk allele would be the first germline entry point into the TLR2-KLK5-LL-37 axis. An exploratory analysis of the subtype-spanning biopsy series (GEO GSE65914) asks whether each locus gene is differentially expressed in lesional skin by subtype, and whether TLR1 and TLR2 are co-expressed there. This hypothesis has no causal edges of its own; it concerns the genetic entries. Downstream causal edges that belong to it would opt in via hypothesis_groups: [gwas_loci_lesional_expression].

Exploratory dataset run: geo:GSE65914 with target genes HLA-DRA, BTNL2, HLA-DRB1, HLA-DQB1, HLA-DQA1, IL13, IRF1, TLR1, TLR2, IRF4, HERC2, OCA2, SLC45A2. The MVP loci come from the GWAS Catalog (GCST90476178), which this repository cannot yet cite directly (see the dbgap:phs001672 dataset record).

Deep research

OpenScientist citations 3 citations 2026-09-06T18:38:23.791222

Show evidence (2 references)

PMID:29771307 SUPPORT Human Clinical

"Genes within three loci (PSMB9-HLA-DMA, HERC-OCA2 and NRX3-DIO2) were differentially expressed in a previously published clinical rosacea transcriptomics study that compared lesional to non-lesional samples."

The precedent: GWAS loci already shown to change expression in lesional skin, motivating the same test for the remaining loci.

PMID:25695682 SUPPORT Human Clinical

"Exploratory immunohistochemical analysis of HLA-DRA and BTNL2 expression in papulopustular rosacea lesions from six individuals, including one with the rs763035 variant, revealed staining in the perifollicular inflammatory infiltrate of rosacea for both proteins."

Protein-level lesional expression for the lead HLA-region locus.

Rhinophyma fibroblasts are an inflammation-associated activated state lacking the POSTN/CTHRC1 scar-persistence program, not a scar-type myofibroblast

phyma_fibroblast_identity EMERGING Phymatous Rosacea

Evidence balance 2 support

Single-cell transcriptomics of papulopustular rosacea identifies an expanded pro-inflammatory fibroblast population, marked by PTGDS, as the leading source of inflammatory and vasodilatory signals, and fibroblast depletion or PTGDS knockdown blocks disease in mice. Rhinophyma, the end-stage phymatous lesion, is clinically fibrotic yet reverts toward normal after surgical debulking, unlike hypertrophic scar. The hypothesis is that the phyma fibroblast is the same inflammation-driven state as the papulopustular fibroblast, persisting rather than transitioning to a scar-type myofibroblast, which would explain both the reversibility and why the fibrotic remodeling node feeds phymatous change. An exploratory comparison of the rhinophyma versus hypertrophic scar versus healthy skin single-cell atlas (ArrayExpress E-MTAB-16629) against the published papulopustular fibroblast markers asks whether rhinophyma fibroblasts carry the PTGDS pro-inflammatory signature or the ACTA2/COL1A1 myofibroblast signature of scar. Downstream causal edges that belong to this hypothesis opt in via hypothesis_groups: [phyma_fibroblast_identity].

Exploratory dataset run on arrayexpress:E-MTAB-16629 (kb/hypotheses/Rosacea/phyma_fibroblast_identity/, assessed PARTIALLY_SUPPORTED): in the one rhinophyma donor, PTGDS is lowest in rhinophyma fibroblasts (5.0% positive) and highest in healthy fibroblasts (54.5%), tracks the quiescent markers CFD and APOD, and the PTGDS-high rhinophyma cells are endothelial, so the PTGDS marker from papulopustular disease does not transfer and was removed from the label. Rhinophyma fibroblasts are ACTA2-activated but POSTN- and CTHRC1-low (3.1% and 8.0% positive versus 46.4% and 43.4% in hypertrophic scar) with CCL19, CXCL12 and CCL2 above scar levels, supporting the non-scar-myofibroblast identity that the label now states. One donor per condition, marker-score lineage assignment and a proxy signature bound every claim. The papulopustular single-cell data of Chen et al. have no public accession, so a joint embedding, the analysis that would settle this, was not possible.

Pathograph links

Pro-inflammatory Fibroblast Expansion -> Neurovascular vasodilation DIRECT Fibroblasts are the leading cell type producing vasodilative signals in rosacea skin.

Pro-inflammatory Fibroblast Expansion -> Immune cell infiltration INDIRECT KNOWN INTERMEDIATES Fibroblast-derived pro-inflammatory signals sustain lesional inflammation; removing fibroblasts or PTGDS blocks rosacea-like disease in mice. Intermediates: fibroblast-derived cytokine and chemokine signaling

Deep research

OpenScientist citations 11 citations 2026-09-06T18:50:42.850829

Show evidence (2 references)

PMID:39384741 SUPPORT Human Clinical

"The papulopustular rosacea is featured by expansion of pro-inflammatory fibroblasts, Schwann, endothelial and macrophage/dendritic cells."

The papulopustular fibroblast population the phyma fibroblast is to be compared against.

PMID:39384741 SUPPORT Model Organism

"Depletion of fibroblasts or knockdown of PTGDS, a gene specifically upregulated in fibroblasts, blocks rosacea development in mice."

Establishes PTGDS as the marker and the fibroblast as causal in the inflammatory subtype.

Discussions and Knowledge Gaps

Can the neurovascular arm of rosacea (TRP-channel sensory activation, CGRP and substance P release, and the vasodilation behind flushing and burning) be modelled in a human non-animal system, given that every current NAM lacks sensory neurons and perfused microvessels?

KNOWLEDGE GAP OPEN gap_rosacea_innervated_vascularized_nam

Attached to

pathophysiology#TRP and neuropeptide signaling pathophysiology#Neurovascular vasodilation experimental_models#

The three NAMs in this entry cover the innate-immune and sebaceous arms: the papulopustular explant keeps the resident multicellular circuit, the SZ95 co-culture isolates the mite-sebocyte interface, and HaCaT keratinocytes reproduce TLR2 induction. None contains sensory neurons or a perfused vascular bed, so the flushing and burning phenotypes, and the fibroblast-derived vasodilatory signalling that single-cell profiling places upstream of them, can only be studied in the facial LL-37 mouse. Generic innervated and vascularized skin-on-chip platforms exist, but no rosacea-specific application has been published, so this is recorded as an absence of evidence rather than a mismatch between model and human.

Proposed experiments

Innervated, vascularized skin-on-chip built from rosacea fibroblasts

exp_rosacea_innervated_vascularized_skin_chip

Reconstruct full-thickness skin on a perfusable microfluidic chip with a dermal microvessel network, patient-derived (or PTGDS-high pro-inflammatory) dermal fibroblasts, keratinocytes, mast cells and iPSC-derived TRPV1-positive sensory neurons; challenge with LL-37, heat and capsaicin; measure neuropeptide release, vessel dilation and permeability, and mast cell degranulation, with and without a CGRP receptor antagonist.

Perturbations

LL-37 challenge

pathophysiology#LL-37 generation

Apply the processed cathelicidin peptide at lesional concentrations to the epidermal compartment.

Heat and capsaicin challenge

pathophysiology#TRP and neuropeptide signaling

Thermal ramp and capsaicin to activate TRPV1 on the innervating sensory neurons.

Readouts

CGRP and substance P in the dermal effluent

pathophysiology#TRP and neuropeptide signaling

Direction: INCREASED

Interpretation: Neuropeptide release from innervating sensory neurons on challenge.

Microvessel diameter and permeability

pathophysiology#Neurovascular vasodilation

Direction: INCREASED

Interpretation: Live-imaged vasodilation and dextran leak, the tissue-level readout of flushing.

Controls

Neuron-free chips

Otherwise identical chips built without sensory neurons, to show which readouts require innervation.

Control-donor fibroblast arm

Chips built with fibroblasts from healthy donors to test whether the rosacea fibroblast state is required for amplification.

Vehicle challenge

Buffer-only challenge to establish the baseline vessel and neuropeptide response of the platform.

Decision criterion

A reproducible, antagonist-sensitive coupling from neuropeptide release to vessel dilation in at least three independent chip builds.

Would support

pathophysiology#TRP and neuropeptide signaling pathophysiology#Neurovascular vasodilation

Would refute

pathophysiology#Neurovascular vasodilation

Supporting outcome

LL-37, heat or capsaicin evokes CGRP release and vessel dilation that a CGRP receptor antagonist blocks, and rosacea-derived fibroblasts amplify the response relative to control-donor fibroblasts.

Refuting outcome

Vessel dilation on challenge is unchanged by building the chip without sensory neurons or by CGRP receptor antagonism, placing the vasodilation outside the neuropeptide arm this experiment models.

Posed after the 2026-09 NAM curation. Generic innervated skin-on-chip and vascularized skin-equivalent platforms are published outside rosacea; the gap is their application to this disease, not their existence.

Show evidence (2 references)

PMID:39384741 SUPPORT Human Clinical

"Most importantly, fibroblasts are identified as the leading cell type producing pro-inflammatory and vasodilative signals in rosacea."

The vasodilatory program originates in a dermal cell type, so a model of it needs fibroblasts, vessels and nerves together, which no current rosacea NAM provides.

PMID:36517318 SUPPORT Model Organism

"Increased expression of the temperature-sensitive receptors TRPV4 and TRPM8 was found in pruritic mouse skin and TG and human skin samples."

The sensory-ganglion readout that makes the facial mouse model the only current system for this arm.

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Pathophysiology

Skin barrier dysfunction

Epidermal barrier disruption amplifies inflammatory signaling in rosacea and serves as an early permissive event for downstream innate immune activation.

keratinocyte CL:0000312

establishment of skin barrier GO:0061436

Downstream

Pro-cathelicidin transcription Barrier-disrupting triggers increase keratinocyte pro-cathelicidin transcription.

STAT3-mediated cytokine signaling Barrier injury activates a keratinocyte cytokine-signaling program centered on STAT3.

Show evidence (1 reference)

PMID:35392024 SUPPORT Human Clinical

"our results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea partly by activating STAT3-mediated cytokine signal pathways in keratinocytes."

This study establishes barrier dysfunction as a disease-amplifying mechanism in rosacea.

Demodex Folliculorum Proliferation

Demodex folliculorum mite density in facial pilosebaceous units is substantially increased in rosacea skin relative to healthy controls. Mites secrete bioactive molecules that modulate Toll-like receptor signaling in sebocytes and are increasingly recognized as a trigger of the innate immune inflammatory cascade rather than an incidental commensal finding.

pilosebaceous unit UBERON:0011932

Experimental models

SZ95 sebocyte and live Demodex mite co-culture CO CULTURE Mite number is the controlled input, so the system tests what a rising mite load does to the sebocyte rather than reproducing follicular proliferation itself.

Animal models

Demodex mite injection rabbit model Rabbit perturbs A bolus of injected mites stands in for follicular mite proliferation, so the model perturbs the Demodex node rather than reproducing gradual pilosebaceous colonization.

Downstream

TLR2 upregulation Demodex mites secrete bioactive molecules that modulate Toll-like receptor signaling and increase TLR2 receptor expression, initially characterized in sebocytes, contributing to the broader innate immune TLR2 activation seen in rosacea skin. The supporting measurement is in sebocytes while the target node is scoped to keratinocytes, so the edge carries an extrapolation across cell type; that is an epistemic caveat, recorded here and in the evidence item's directness, not a step in the causal chain.

Sebaceous gland dysfunction Live Demodex mites directly stimulate sebocytes in culture, altering Toll-like receptor pathway gene and protein expression and inducing proinflammatory cytokine secretion, implicating the sebaceous unit as a site of mite-host immune interaction.

Show evidence (2 references)

PMID:23171449 SUPPORT Human Clinical

"D. folliculorum density was 5.7 times higher in rosacea patients than in healthy volunteers."

Quantitative PCR study establishing markedly increased Demodex folliculorum density as a feature of rosacea skin.

PMID:33095403 SUPPORT Human Clinical

"The Demodex mite is beginning to be accepted as one of the triggers of this inflammatory cascade, and its proliferation as a marker of rosacea"

Review supporting Demodex proliferation as a recognized trigger of the rosacea inflammatory cascade rather than an incidental finding.

Pro-cathelicidin transcription

Keratinocytes in rosacea upregulate pro-cathelicidin transcription, creating substrate for downstream proteolytic generation of inflammatory peptides.

keratinocyte CL:0000312

Downstream

LL-37 generation Increased pro-cathelicidin availability supports downstream formation of LL-37 after proteolytic processing.

Show evidence (1 reference)

PMID:28150107 SUPPORT Human Clinical

"The sequence of innate immune activation in rosacea starts with factors increasing keratinocyte transcription of pro-cathelicidin"

This review explicitly places pro-cathelicidin transcription near the start of rosacea innate immune activation.

TLR2 upregulation

Keratinocyte TLR2 expression is increased in rosacea and sensitizes skin to environmental and microbial stimuli.

keratinocyte CL:0000312

Experimental models

SZ95 sebocyte and live Demodex mite co-culture CO CULTURE Mite-secreted molecules change TLR2 receptor expression in sebocytes, the cell-type-specific counterpart of the keratinocyte TLR2 rise the node describes.

HaCaT keratinocytes under simulated rosacea conditions CELL LINE Keratinocyte TLR2 and S100A9 protein rise under the simulated rosacea milieu, matching the lesional TLR2 increase in patient skin.

Downstream

KLK5/KLK7 activation Increased TLR2 signaling promotes activation of kallikrein-family serine proteases.

Show evidence (1 reference)

PMID:39823143 SUPPORT In Vitro

"Specifically, Toll-like receptor 2 (TLR2) and S100A9 proteins were upregulated, potentially promoting these processes."

This study supports increased TLR2 expression as part of rosacea inflammatory activation.

KLK5/KLK7 activation

Kallikrein-family serine proteases are activated downstream of TLR2 and participate in cathelicidin processing.

Downstream

LL-37 generation Activated KLK5/KLK7 cleave pro-cathelicidin to generate LL-37 and related peptides.

Show evidence (1 reference)

PMID:28150107 SUPPORT Human Clinical

"the serine proteases of the KLK family, KLK5 and KLK7 (activation mediated by TLR-2, which is upregulated by environmental and microbial stimuli)"

This review identifies KLK5/KLK7 as activated proteases in rosacea innate immune signaling.

LL-37 generation

Proteolytic cathelicidin processing yields LL-37 and related peptides with inflammatory and angiogenic activity.

LL-37 drives papulopustular lesions through NLRP3 inflammasome activation and IL-1beta maturation

inflammatory response GO:0006954 angiogenesis GO:0001525

Animal models

LL-37 intradermal injection mouse model Mouse perturbs Exogenous LL-37 substitutes for endogenous KLK5-mediated cathelicidin processing, so the model enters the pathway at the LL-37 step rather than recapitulating its generation.

Downstream

NLRP3 Inflammasome Activation LL-37 activates the NLRP3 inflammasome, among other downstream pathways, driving pro-inflammatory cytokine production; in mice the LL-37-induced inflammatory infiltrate is NLRP3-dependent.

Mast cell-mediated amplification Cathelicidin signaling recruits mast-cell-dependent amplification of inflammation and vascular reactivity.

Angiogenic vascular remodeling LL-37 and related peptides promote angiogenic changes in cutaneous vasculature.

Th1/Th17 adaptive inflammation LL-37-exposed keratinocytes induce chemokine programs that recruit pathogenic T cells and strengthen adaptive inflammatory polarization.

Show evidence (3 references)

PMID:28150107 SUPPORT Human Clinical

"This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"

This review identifies LL-37 generation as a key inflammatory and angiogenic step in rosacea.

PMID:40835085 SUPPORT In Vitro

"Abnormal overexpression of human antimicrobial peptide LL-37 is a hallmark of rosacea."

This study reinforces LL-37 overexpression as a central proximal mechanism in rosacea biology.

PMID:41087666 SUPPORT Model Organism

"Both STING antagonist H-151 and LAPTM5 knockdown alleviate LL-37-induced rosacea-like phenotypes."

This model-organism evidence supports LL-37 as a proximal inducer of rosacea-like inflammatory disease programs.

Mast cell-mediated amplification

Mast cells amplify cathelicidin-initiated inflammation and increase local vasodilation within rosacea lesions.

mast cell CL:0000097

Downstream

Neurovascular vasodilation Mast-cell activation promotes vasodilatory responses in affected skin.

Show evidence (1 reference)

PMID:28150107 SUPPORT Human Clinical

"Mast cells are pivotal mediators of cathelicidin-initiated skin inflammation—amplifying inflammation, vasodilation, and generation of LL-37"

This review places mast cells in an amplification loop that increases inflammatory and vascular disease activity.

STAT3-mediated cytokine signaling

Keratinocyte STAT3-centered cytokine signaling links barrier injury to inflammatory persistence and immune-cell recruitment.

keratinocyte CL:0000312

cytokine-mediated signaling pathway GO:0019221

Downstream

Immune cell infiltration STAT3 activation promotes immune-cell accumulation within rosacea lesions.

Show evidence (1 reference)

PMID:35392024 SUPPORT Human Clinical

This study identifies STAT3-mediated cytokine signaling as a key inflammatory amplifier in rosacea.

ACSL5-Mediated Lipid Metabolism Dysregulation

Transcriptomic profiling of erythematotelangiectatic rosacea (ETR) skin identifies differentially expressed genes enriched in lipid metabolism pathways, with ACSL5 and ACADVL nominated as hub genes by network analysis. This is a single-study, emerging finding rather than an established mechanism.

Lipid-metabolic reprogramming centred on ACSL5 accompanies, and may promote, macrophage infiltration in erythematotelangiectatic rosacea

Downstream

Immune cell infiltration In a rosacea mouse model, ACSL5 upregulation co-localizes with increased M1 macrophage infiltration, suggesting a mechanistic link between lipid-metabolic dysregulation and macrophage-driven inflammation, though the finding is correlative (co-localization) rather than a demonstrated causal perturbation.

Show evidence (1 reference)

PMID:40195491 SUPPORT Human Clinical

Transcriptomic profiling of patient ETR skin samples supports lipid metabolism dysregulation, centered on ACSL5/ACADVL, as a feature of this rosacea subtype.

NLRP3 Inflammasome Activation

Rosacea skin over-expresses inflammasome components (NLRP3/NALP-3, caspase-1) together with IL-1beta, most strongly in papulopustular disease. Reviews place the inflammasome downstream of LL-37 as one route from cathelicidin signaling to IL-1beta maturation and the neutrophilic papulopustular lesion; the paired transcriptomic and proteomic explant dataset geo:GSE155141 in this entry independently implicates IL-1beta as a central lesional mediator.

LL-37 drives papulopustular lesions through NLRP3 inflammasome activation and IL-1beta maturation

NLRP3 inflammasome complex assembly GO:0044546 ↑ INCREASED interleukin-1 beta production GO:0032611 ↑ INCREASED

Experimental models

Paired lesional and non-lesional papulopustular rosacea skin explants OTHER Exogenous IL-1beta applied to non-lesional explants perturbs the IL-1 arm downstream of the inflammasome; the dataset-analysis run on this series found IL-1beta induces NLRP3 transcription in non-lesional tissue while the inflammasome module is not elevated at steady state in lesional explants.

Downstream

Papulopustular inflammation Inflammasome-processed IL-1beta contributes to the neutrophilic inflammatory lesion; inflammasome gene expression is highest in the papulopustular subtype.

Show evidence (2 references)

PMID:23171449 SUPPORT Human Clinical

"Skin sample analysis showed a higher expression of genes encoding pro-inflammatory cytokines (Il-8, Il-1b, TNF-a) and inflammasome-related genes (NALP-3 and CASP-1) in rosacea, especially PPR."

Direct measurement of NALP-3 (NLRP3) and CASP-1 over-expression in rosacea facial skin samples.

PMID:33745908 SUPPORT Model Organism

"LL-37-induced rosacea-like skin inflammation was significantly abrogated in Nlrp3-deficient mice."

Establishes NLRP3 as required for the rosacea-like inflammatory phenotype in the LL-37 model, and the same study shows the NLRP3 inhibitor MCC950 reduces it.

Pro-inflammatory Fibroblast Expansion

Single-cell transcriptomics of lesional facial skin (131,243 cells from nine women with rosacea and three controls) identifies fibroblasts as the leading source of pro-inflammatory and vasodilatory signals, with expansion of a pro-inflammatory fibroblast population in papulopustular disease. Fibroblast depletion, or knockdown of the fibroblast-specific gene PTGDS, blocks rosacea-like disease in mice. This reframes the keratinocyte-centred TLR2-KLK5-LL-37 model as a multicellular circuit in which dermal fibroblasts amplify both inflammation and vasodilation.

Rhinophyma fibroblasts are an inflammation-associated activated state lacking the POSTN/CTHRC1 scar-persistence program, not a scar-type myofibroblast

pro-inflammatory dermal fibroblast CL:0000057

Downstream

Neurovascular vasodilation Fibroblasts are the leading cell type producing vasodilative signals in rosacea skin.

Immune cell infiltration Fibroblast-derived pro-inflammatory signals sustain lesional inflammation; removing fibroblasts or PTGDS blocks rosacea-like disease in mice.

Show evidence (2 references)

PMID:39384741 SUPPORT Human Clinical

"The papulopustular rosacea is featured by expansion of pro-inflammatory fibroblasts, Schwann, endothelial and macrophage/dendritic cells."

Single-cell census documenting the pro-inflammatory fibroblast expansion in papulopustular lesions.

PMID:39384741 SUPPORT Human Clinical

"Most importantly, fibroblasts are identified as the leading cell type producing pro-inflammatory and vasodilative signals in rosacea."

Identifies fibroblasts as the dominant signal-producing population.

Immune cell infiltration

Rosacea lesions show increased immune-cell infiltration that reinforces inflammatory lesion formation.

Animal models

LL-37 intradermal injection mouse model Mouse recapitulates Dermal inflammatory-cell aggregation with epidermal and dermal thickening after repeated LL-37 injection.

Downstream

Papulopustular inflammation Increased lesional immune infiltration supports development of inflammatory papules and pustules.

Show evidence (1 reference)

PMID:35392024 SUPPORT Human Clinical

"The XCell immune cell assays showed that the increased immune infiltration with SBD."

This transcriptomic analysis supports increased immune-cell infiltration in rosacea with barrier dysfunction.

Th1/Th17 adaptive inflammation

Chemokine and cytokine networks in rosacea polarize adaptive immunity toward Th1/Th17 inflammatory programs.

inflammatory response GO:0006954

Downstream

Papulopustular inflammation Th1/Th17-skewed adaptive inflammation contributes to inflammatory papulopustular lesions.

Show evidence (2 references)

PMID:28150107 SUPPORT Human Clinical

"Chemokine and cytokine signals interact to generate a Th1/Th17-polarized adaptive immune response in rosacea"

This review supports a Th1/Th17-polarized adaptive inflammatory response in rosacea.

PMID:40835085 SUPPORT In Vitro

"T-cell recruiting chemokine CXCL10 turns out to be the most abundant inflammatory mediator overexpressed upon LL-37 exposure."

This supports a chemokine-driven adaptive immune arm linking keratinocyte activation to pathogenic T-cell recruitment.

TRP and neuropeptide signaling

TRP-channel activation and neuropeptide signaling form a neurocutaneous branch of rosacea pathophysiology that increases vascular reactivity.

neuropeptide signaling pathway GO:0007218

Animal models

Facial LL-37 injection mouse model with trigeminal readouts Mouse recapitulates Facial LL-37 lesions are accompanied by increased TRPV4 and TRPM8 in skin and in the trigeminal ganglion, with pruritus behaviour, so the model reports the sensory-neuron arm of the neurovascular program at its anatomically correct site.

Downstream

Neurovascular vasodilation TRP and neuropeptide signaling promote exaggerated vasodilatory responses in rosacea skin.

Show evidence (1 reference)

PMID:34035646 SUPPORT Human Clinical

"Recognized mechanisms include the innate immune system, with the implication of Toll-like receptors (TLRs) and cathelicidins; neurovascular deregulation involving vascular endothelial growth factor (VEGF), transient receptor potential (TRP) ion channels, and neuropeptides"

This review identifies TRP and neuropeptides as part of the neurovascular arm of rosacea pathophysiology.

Neurovascular vasodilation

Exaggerated vasodilation is a proximal vascular event that drives flushing and contributes to persistent background erythema.

Computational models

Rosacea Innate-Immune Axis Boolean Model BOOLEAN NETWORK Python (standard library and PyYAML) Reproduced as the disjunction of its three curated upstream edges (mast-cell amplification, fibroblast expansion, TRP and neuropeptide signaling), gated by topical brimonidine.

Downstream

Flushing Vasodilatory surges produce episodic flushing.

Persistent centrofacial erythema Recurrent vasodilatory instability contributes to chronic background centrofacial erythema.

Show evidence (1 reference)

PMID:28150107 SUPPORT Human Clinical

"while the multifactorial pathology of rosacea is thought to involve both vasoactive and neurocutaneous mechanisms."

This overview supports a vasoreactive proximal mechanism in rosacea.

Angiogenic vascular remodeling

Angiogenic signaling contributes to persistent vascular remodeling and visible superficial telangiectatic change.

angiogenesis GO:0001525

Animal models

LL-37 intradermal injection mouse model Mouse recapitulates Long-term LL-37 induction produces dermal angiogenesis alongside skin thickening.

Downstream

Facial telangiectasia Persistent angiogenic remodeling contributes to telangiectatic centrofacial vessels.

Persistent centrofacial erythema Remodeling of superficial vasculature helps sustain background facial erythema.

Show evidence (2 references)

PMID:28150107 SUPPORT Human Clinical

"This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"

This supports angiogenic signaling as a discrete downstream consequence of cathelicidin pathway activation.

PMID:40567003 SUPPORT Computational

"angiogenesis and neutrophil activation may contribute to persistent erythema and a large number of papules and pustules in the severe stage of rosacea."

This molecular subtyping study supports angiogenesis as a driver of persistent erythema and lesion-rich severe rosacea.

Papulopustular inflammation

Convergent innate, adaptive, and keratinocyte inflammatory programs produce inflammatory papules and pustules in papulopustular rosacea.

inflammatory response GO:0006954

Experimental models

Paired lesional and non-lesional papulopustular rosacea skin explants OTHER Lesional explants carry the in vivo papulopustular inflammatory program into culture; MAPK and TNF signaling are the most up-regulated pathways versus paired non-lesional tissue.

Animal models

Demodex mite injection rabbit model Rabbit partially recapitulates Mite injection produces erythematous papules and telangiectasia with a granuloma-like histology.

Computational models

Rosacea Innate-Immune Axis Boolean Model BOOLEAN NETWORK Python (standard library and PyYAML) The node is reproduced as the disjunction of its three curated upstream edges, so the model reproduces which arms can produce the lesion but not how much of each is needed, nor its time course.

Downstream

Papules Inflammatory lesion formation produces papular eruptions.

Pustules Ongoing inflammatory lesion formation produces pustules.

Show evidence (1 reference)

PMID:39823143 SUPPORT Human Clinical

"Transcriptomic analysis revealed significantly elevated expression of inflammatory-related genes in rosacea patients."

This study supports a lesion-forming inflammatory state in rosacea skin.

Sebaceous gland dysfunction

Dysfunction of cutaneous sebaceous glands is recognized as part of the multifactorial tissue biology of rosacea.

Experimental models

SZ95 sebocyte and live Demodex mite co-culture CO CULTURE Shows that the sebocyte is an immune-reactive participant that mites can push into cytokine production, one component of sebaceous-unit dysfunction.

Downstream

Sebaceous gland and soft tissue hyperplasia/fibrosis In advanced disease, altered sebaceous-unit biology can progress to hyperplastic and fibrotic phymatous tissue remodeling.

Show evidence (1 reference)

PMID:34035646 SUPPORT Human Clinical

This review identifies sebaceous gland dysfunction as a discrete component of rosacea pathophysiology.

Meibomian gland dysfunction

Ocular rosacea includes meibomian gland dysfunction as part of its site-specific pathophysiology.

Downstream

Ocular surface and eyelid inflammation Meibomian-gland disease contributes to chronic inflammatory involvement of the eyelids and ocular surface.

Show evidence (1 reference)

PMID:34035646 SUPPORT Human Clinical

This review identifies meibomian gland dysfunction as part of ocular rosacea biology.

Ocular surface and eyelid inflammation

Ocular rosacea produces chronic inflammatory involvement of the eyelids and ocular surface, with posterior blepharitis as a characteristic clinical expression.

inflammatory response GO:0006954

Downstream

Blepharitis Chronic eyelid inflammation manifests clinically as posterior blepharitis.

Show evidence (1 reference)

PMID:40522449 SUPPORT Human Clinical

"Ocular rosacea is a chronic inflammatory disease that affects the surface of the eye and the eyelids."

This review supports ocular rosacea as an inflammatory disease of the eyelids and ocular surface.

Fibrotic dermal remodeling

Advanced rosacea can shift toward a fibrotic remodeling program in which vascular changes are coupled to connective-tissue fibrosis.

Animal models

LL-37 intradermal injection mouse model Mouse partially recapitulates Prolonged LL-37 dosing produces dermal collagen deposition with alpha-SMA and COL1 induction that persists after injections stop.

Downstream

Sebaceous gland and soft tissue hyperplasia/fibrosis Fibrotic remodeling progresses to phymatous tissue overgrowth involving sebaceous units and surrounding soft tissue.

Show evidence (2 references)

PMID:25151931 SUPPORT Human Clinical

"Finaly, rhinophyma is linked to both vascular changes and activation of fibrosis, involving TGF beta."

This review supports fibrosis as a specific mechanism underlying rhinophyma development.

PMID:41139274 SUPPORT In Vitro

"GZMK also promoted cell proliferation and inflammatory factors (including IL-1β, IL-6, and TNFα) production in fibroblasts through activating the NF-κB pathway in vitro."

This directly supports fibroblast proliferative and inflammatory programs that can feed fibrotic remodeling in advanced rosacea.

Sebaceous gland and soft tissue hyperplasia/fibrosis

Rhinophyma reflects progressive hypertrophic remodeling of sebaceous glands and adjacent soft tissue in the nose.

Animal models

LL-37 intradermal injection mouse model Mouse partially recapitulates Long-term LL-37 induction produces sebaceous gland hypertrophy with dermal thickening, the earliest tissue-level analogue of phymatous change.

Downstream

Phymatous change of the nose Hyperplastic and fibrotic tissue overgrowth produces the bulbous, progressively deformed nasal phenotype of rhinophyma.

Show evidence (1 reference)

PMID:19428039 SUPPORT Human Clinical

"Rhinophyma is an irregular and progressive nasal hypertrophy, due to hyperplasia and fibrosis of the sebaceous glands and surrounding soft tissues."

This abstract defines rhinophyma in terms of sebaceous-gland and soft tissue hyperplasia/fibrosis.

✶

Histopathology

Dermal vascular endothelial Angiopoietin 2 and Tie2 overexpression

Lesional erythematotelangiectatic and papulopustular rosacea skin shows increased Angiopoietin 2 and Tie2 staining in endothelial cells of dermal vessels compared with non-lesional skin, supporting a vascular remodeling-associated histopathology pattern.

Show evidence (1 reference)

PMID:41562711 SUPPORT Human Clinical

"Significantly increased expression of Tie2 and Angiopoietin 2 in the endothelial cells of the dermal vessels in rosacea skin vs. non-lesional skin (100% and 33.3% for Tie2, and 100% and 50% for Angiopoietin 2) was observed."

This provides direct biopsy-level immunohistochemical evidence for altered dermal vascular endothelium in rosacea lesions.

Early dermal fibrotic remodeling

Fibrotic remodeling is detectable in rosacea skin biopsies even at inflammation-dominant stages, indicating that tissue-remodeling changes begin before fully developed phymatous disease.

Show evidence (1 reference)

PMID:41800255 SUPPORT Human Clinical

"single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and histological staining of skin biopsies demonstrated that fibrotic remodeling was already evident at inflammation-dominant stages"

This study directly supports fibrosis as an observable tissue-level change in rosacea biopsies, not only in late rhinophyma.

Sebaceous gland and surrounding soft tissue hyperplasia with fibrosis

Rhinophyma shows hypertrophic remodeling of sebaceous glands and adjacent soft tissue accompanied by fibrosis, forming the core microscopic pattern of phymatous rosacea.

Show evidence (1 reference)

PMID:19428039 SUPPORT Human Clinical

"Rhinophyma is an irregular and progressive nasal hypertrophy, due to hyperplasia and fibrosis of the sebaceous glands and surrounding soft tissues."

This abstract directly supports sebaceous gland hyperplasia with fibrosis as a defining microscopic tissue-remodeling feature of rhinophyma.

Leaky vascular architecture in rhinophyma tissue

Rhinophyma tissue shows an abnormal vascular architecture with leaky vessel profiles rather than the stromal-enveloped vascular pattern seen in hypertrophic scars.

Show evidence (1 reference)

PMID:41909715 SUPPORT Human Clinical

"Vascular structures in hypertrophic scar tissues are enveloped by a significant number of stromal cells, in contrast to the leaky vascular profiles observed in rhinophyma tissues."

This study supports a distinctive vascular tissue architecture in rhinophyma that fits the disease's vascular-remodeling phenotype.

Immune-cell-rich rhinophyma tissue

Rhinophyma tissue contains a relatively expanded immune-cell compartment, consistent with persistent inflammatory remodeling in phymatous disease.

Show evidence (1 reference)

PMID:41909715 SUPPORT Human Clinical

"the number of immune cells in rhinophyma is significantly higher than in hypertrophic scar tissues."

This supports immune-cell enrichment as a tissue-level feature of rhinophyma.

Eyelid tissue lymphoedema in ocular rosacea

In rare ocular rosacea with persistent peri-orbital swelling, eyelid debulking biopsy can show rosacea-associated inflammatory change with superimposed lymphoedematous tissue remodeling.

Show evidence (1 reference)

PMID:41058755 SUPPORT Human Clinical

"Histopathological analysis of the debulking biopsy confirmed the diagnosis of rosacea, with additional features indicative of lymphoedema."

This provides direct biopsy-level support for lymphoedematous tissue change in a rare ocular rosacea presentation.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Cardiovascular 2

Persistent centrofacial erythema VERY_FREQUENT HP:0001041

Persistent background erythema of the central face is a core diagnostic phenotype in modern phenotype-led rosacea classification.

Show evidence (1 reference)

PMID:27718519 SUPPORT Human Clinical

"The following two features were independently considered diagnostic for rosacea: (i) persistent, centrofacial erythema associated with periodic intensification; and (ii) phymatous changes."

ROSCO identifies persistent centrofacial erythema as one of the two diagnostic phenotypes for rosacea.

Facial telangiectasia FREQUENT HP:0007380

Show evidence (1 reference)

PMID:37626650 SUPPORT Human Clinical

"Rosacea is a chronic inflammatory skin disease characterized by recurrent erythema, flushing, telangiectasia, papules, pustules, and phymatous changes in the central area of the face."

This review includes telangiectasia among the central defining manifestations of rosacea.

Eye 1

Blepharitis OCCASIONAL HP:0000498

Ocular rosacea often presents with eyelid margin inflammation.

Show evidence (1 reference)

PMID:40522449 SUPPORT Human Clinical

"It is characterized by bilateral chronic posterior blepharitis and meibomitis, which can involve the entire surface of the eye, including the cornea, during the course of the disease."

This directly supports chronic posterior blepharitis as a hallmark ocular phenotype of ocular rosacea.

Head and Neck 3

Phymatous change of the nose OCCASIONAL Bulbous nose HP:0000414

Phymatous rosacea is most often expressed as progressive tissue thickening of the nose (rhinophyma).

Show evidence (1 reference)

PMID:27718519 SUPPORT Human Clinical

"The following two features were independently considered diagnostic for rosacea: (i) persistent, centrofacial erythema associated with periodic intensification; and (ii) phymatous changes."

ROSCO identifies phymatous change as the second independently diagnostic phenotype of rosacea.

Facial edema VERY_RARE HP:0000282

A rare rosacea-associated lymphedematous presentation, often termed Morbihan disease, causes chronic persistent facial swelling.

Show evidence (1 reference)

PMID:41426892 SUPPORT Human Clinical

"Morbihan disease, also known as rosacea-associated solid facial edema, is a rare and chronic condition that presents with persistent facial swelling and often proves difficult to treat."

This directly supports persistent facial edema as a rare rosacea-associated phenotype.

Upper eyelid edema HP:0012724

Ocular rosacea can rarely present with persistent peri-orbital swelling, sometimes accompanied by secondary ptosis. Frequency band omitted: the sole source is a single case report, which establishes that the presentation occurs but cannot support any frequency band, not even VERY_RARE, since an n-of-1 report carries no denominator.

Show evidence (1 reference)

PMID:41058755 SUPPORT Human Clinical

"A 64-year-old Caucasian man presented with a 9-month history of persistent painless swelling of the right upper eyelid and secondary ptosis."

This case report supports persistent upper-eyelid edema as a rare ocular manifestation of rosacea.

Immune 1

Pustules FREQUENT HP:0200039

Show evidence (1 reference)

PMID:28150107 SUPPORT Human Clinical

"Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."

This overview identifies papulopustular lesions as part of the core clinical spectrum of rosacea.

Integument 2

Flushing FREQUENT HP:0031284

Episodic flushing commonly accompanies the vascular phenotype.

Show evidence (1 reference)

PMID:28150107 SUPPORT Human Clinical

"Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."

This overview identifies flushing as a characteristic clinical manifestation of rosacea.

Papules FREQUENT Erythematous papule HP:0030350

Show evidence (1 reference)

PMID:28150107 SUPPORT Human Clinical

"Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."

This overview identifies inflammatory papules as a characteristic lesion type in rosacea.

🧬

Genetic Associations

IRF1 (MR-supported druggable gene)

Gene: IRF1 hgnc:6116

Show evidence (1 reference)

PMID:40635520 SUPPORT Computational

"MR and SMR analyses identified IRF1 and SLC22A5 as druggable genes for rosacea, with Bayesian colocalization strongly supporting shared causal variants."

This directly supports IRF1 as a genetically prioritized therapeutic target in rosacea.

SLC22A5 (MR-supported druggable gene)

Gene: SLC22A5 hgnc:10969

Show evidence (1 reference)

PMID:40635520 SUPPORT Computational

"MR and SMR analyses identified IRF1 and SLC22A5 as druggable genes for rosacea, with Bayesian colocalization strongly supporting shared causal variants."

This directly supports SLC22A5 as a genetically prioritized therapeutic target in rosacea.

GZMK (MR-supported drug target)

Gene: GZMK hgnc:4711

Show evidence (1 reference)

PMID:41139274 SUPPORT Computational

"MR and colocalization identified Granzyme K (GZMK) as a drug target, whose expression increased in the affected samples."

This supports GZMK as a genetically prioritized rosacea target with increased expression in disease-associated samples.

MSR1 (MR-supported risk-promoting biomarker)

Gene: MSR1 hgnc:7376

Show evidence (1 reference)

PMID:40890957 SUPPORT Computational

"Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."

This directly supports MSR1 as the risk-promoting protein among the final MR-prioritized rosacea biomarkers.

ABHD14B (MR-supported protective biomarker)

Gene: ABHD14B hgnc:28235

Show evidence (1 reference)

PMID:40890957 SUPPORT Computational

This supports ABHD14B as one of the final MR-prioritized proteins associated with lower rosacea risk.

CHMP6 (MR-supported protective biomarker)

Gene: CHMP6 hgnc:25675

Show evidence (1 reference)

PMID:40890957 SUPPORT Computational

This supports CHMP6 as one of the final MR-prioritized proteins associated with lower rosacea risk.

DBNL (MR-supported protective biomarker)

Gene: DBNL hgnc:2696

Show evidence (1 reference)

PMID:40890957 SUPPORT Computational

This supports DBNL as one of the final MR-prioritized proteins associated with lower rosacea risk.

MCFD2 (MR-supported protective biomarker)

Gene: MCFD2 hgnc:18451

Show evidence (1 reference)

PMID:40890957 SUPPORT Computational

This supports MCFD2 as one of the final MR-prioritized proteins associated with lower rosacea risk.

HLA-DRA (GWAS susceptibility locus (rs763035, intergenic HLA-DRA/BTNL2))

Gene: HLA-DRA hgnc:4947 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:25695682 SUPPORT Human Clinical

"The confirmed SNP, rs763035 (P=8.0 × 10(-11) discovery group; P=0.00031 replication group), is intergenic between HLA-DRA and BTNL2."

Replicated genome-wide significant association placing the lead rosacea susceptibility variant between HLA-DRA and BTNL2.

PMID:25695682 SUPPORT Human Clinical

Places HLA-DRA protein in the lesional inflammatory infiltrate, linking the locus to the immune-cell infiltration in this entry.

Variants (1)

rs763035

Intergenic common variant between HLA-DRA and BTNL2; the one genome-wide significant SNP from the 23andMe discovery GWAS that replicated in an independent group.

Identifiers: dbSNP:rs763035

BTNL2 (GWAS susceptibility locus (rs763035, intergenic HLA-DRA/BTNL2))

Gene: BTNL2 hgnc:1142 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:25695682 SUPPORT Human Clinical

"The confirmed SNP, rs763035 (P=8.0 × 10(-11) discovery group; P=0.00031 replication group), is intergenic between HLA-DRA and BTNL2."

The replicated lead SNP lies between HLA-DRA and BTNL2, so BTNL2 is a candidate effector gene of the locus.

PMID:25695682 SUPPORT Human Clinical

BTNL2 protein is detected in the lesional perifollicular infiltrate.

HLA-DRB1 (MHC class II risk allele HLA-DRB1*03:01)

Gene: HLA-DRB1 hgnc:4948 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:25695682 SUPPORT Human Clinical

"three HLA alleles, all MHC class II proteins, were significantly associated with rosacea in the discovery group and confirmed in the replication group: HLA-DRB1*03:01 (P=1.0 × 10(-8) discovery group; P=4.4 × 10(-6) replication group)"

Replicated association of the HLA-DRB1*03:01 allele with rosacea.

HLA-DQB1 (MHC class II risk allele HLA-DQB1*02:01)

Gene: HLA-DQB1 hgnc:4944 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:25695682 SUPPORT Human Clinical

"HLA-DQB1*02:01 (P=1.3 × 10(-8) discovery group; P=7.2 × 10(-6) replication group)"

Replicated association of the HLA-DQB1*02:01 allele with rosacea.

HLA-DQA1 (MHC class II risk allele HLA-DQA1*05:01)

Gene: HLA-DQA1 hgnc:4942 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:25695682 SUPPORT Human Clinical

"HLA-DQA1*05:01 (P=1.4 × 10(-8) discovery group; P=7.6 × 10(-6) replication group)"

Replicated association of the HLA-DQA1*05:01 allele with rosacea.

IRF4 (Symptom-severity GWAS locus linked to both pigmentation and immuno-inflammatory phenotypes)

Gene: IRF4 hgnc:6119 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:29771307 SUPPORT Human Clinical

"Further analyses highlighted likely gene regions or effector genes including IRF4 (P = 1.5 × 10-17), a human leukocyte antigen (HLA) region flanked by PSMB9 and HLA-DMB (P = 2.2 × 10-15), HERC2-OCA2 (P = 4.2 × 10-12), SLC45A2 (P = 1.7 × 10-10), IL13 (P = 2.8 × 10-9)"

IRF4 is the strongest symptom-severity locus in this GWAS.

PMID:29771307 SUPPORT Human Clinical

"one has been associated with both categories (IRF4)"

The authors classify IRF4 as bridging skin-pigmentation and immuno-inflammatory phenotypes.

HERC2 (HERC2-OCA2 pigmentation locus associated with symptom severity)

Gene: HERC2 hgnc:4868 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:29771307 SUPPORT Human Clinical

Genome-wide significant symptom-severity association at HERC2-OCA2.

PMID:29771307 SUPPORT Human Clinical

Lesional expression change supports the locus acting in rosacea skin rather than only through constitutive pigmentation.

SLC45A2 (Pigmentation gene associated with symptom severity)

Gene: SLC45A2 hgnc:16472 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:29771307 SUPPORT Human Clinical

"Two of these loci (HERC-OCA2 and SLC45A2) and another precedented variant (rs1805007 in melanocortin 1 receptor) with an association P value just below the significance threshold (P = 1.3 × 10-7) have been previously associated with skin phenotypes and pigmentation"

SLC45A2 is one of the pigmentation loci reaching genome-wide significance for rosacea severity.

IL13 (Immuno-inflammatory GWAS locus associated with symptom severity)

Gene: IL13 hgnc:5973 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:29771307 SUPPORT Human Clinical

Genome-wide significant symptom-severity association at IL13.

PMID:29771307 SUPPORT Human Clinical

"two of these loci are linked to immuno-inflammation phenotypes (IL13 and PSMB9-HLA-DMA)"

The authors classify IL13 as an immuno-inflammatory rosacea locus.

💊

Medical Actions

Trigger avoidance and photoprotection

Baseline management includes avoidance of provoking exposures, gentle skin care, moisturization, and sun protection to reduce flares.

Show evidence (1 reference)

PMID:28150107 SUPPORT Human Clinical

"While standard measures, including avoidance of triggers, gentle cleansers, and moisturizers in combination with sun protection, may mitigate flares, control signs and symptoms in some patients"

This review supports trigger avoidance, gentle skin care, and photoprotection as foundational rosacea management.

Papulopustular-directed pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: metronidazole CHEBI:6909 azelaic acid NCIT:C47407 ivermectin CHEBI:6078 doxycycline CHEBI:50845 isotretinoin NCIT:C603

Papulopustular rosacea is commonly treated with topical metronidazole, azelaic acid, or ivermectin, and in more inflammatory disease with oral doxycycline or isotretinoin.

Mechanism Target:

INHIBITS Demodex Folliculorum Proliferation — Topical acaricidal agents, including ivermectin, are used to reduce Demodex mite density as part of papulopustular rosacea therapy.

Show evidence (1 reference)

PMID:33095403 SUPPORT INDIRECT Human Clinical

"the papulopustules of rosacea can be effectively treated with topical acaricidal agents"

Supports acaricidal treatment as effective against papulopustular rosacea via reduction of Demodex mite burden; ivermectin (already listed among this treatment's agents) has acaricidal activity, so the link to this specific agent is indirect rather than the source naming ivermectin explicitly.

Show evidence (1 reference)

PMID:28150107 SUPPORT Human Clinical

"topical metronidazole, azelaic acid, ivermectin, or oral doxycycline and isotretinoin for papulopustules of rosacea"

This review summarizes standard pharmacologic options used for papulopustular rosacea.

Topical brimonidine therapy

Action: topical pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: brimonidine CHEBI:3175

Persistent background erythema can be treated with topical brimonidine to reduce visible vasodilatory erythema.

Show evidence (1 reference)

PMID:28150107 SUPPORT Human Clinical

"topical brimonidine or intense pulsed light (IPL) for background persistent erythema"

This review identifies brimonidine as a targeted therapy for persistent background erythema.

Vascular light-based therapy

Action: vascular light-based therapy Ontology label: Phototherapy NCIT:C15301

Persistent vascular erythema may also be treated with light-based therapy such as intense pulsed light.

Show evidence (1 reference)

PMID:28150107 SUPPORT Human Clinical

"topical brimonidine or intense pulsed light (IPL) for background persistent erythema"

This review identifies light-based vascular therapy as another targeted approach for persistent erythema.

Cyclosporine eye drops

Action: Pharmacotherapy NCIT:C15986

Agent: cyclosporine CHEBI:4031

Ocular rosacea may require targeted ophthalmic anti-inflammatory therapy such as cyclosporine eye drops.

Show evidence (1 reference)

PMID:28150107 SUPPORT Human Clinical

"cyclosporine eye drops for ocular rosacea"

This review identifies cyclosporine eye drops as a treatment option for ocular rosacea.

Morbihan disease-directed pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: isotretinoin NCIT:C603 triamcinolone NCIT:C901 ketotifen CHEBI:92511

Rosacea-associated solid facial edema may require individualized combination pharmacotherapy centered on isotretinoin and intralesional corticosteroid treatment, with ketotifen used in selected refractory cases.

Target Phenotypes: facial edema HP:0000282

Show evidence (2 references)

PMID:41426892 SUPPORT Human Clinical

"The patient reported partial improvement, most notably with higher isotretinoin dosing and intralesional corticosteroid injections, though intermittent flares persisted."

This supports isotretinoin and intralesional corticosteroid treatment as active components of Morbihan disease management.

PMID:41222206 SUPPORT Human Clinical

"Successful treatment with a series of triamcinolone injections to the upper and lower eyelids was achieved after several unsuccessful therapies."

This independently supports intralesional triamcinolone as a useful treatment option for rosacea-associated solid facial edema.

Laser surgical debulking for rhinophyma

Action: laser surgical procedure Ontology label: Laser Therapy NCIT:C15466

CO2 laser or blue-laser debulking can remove phymatous nasal tissue and improve function and cosmesis in selected rhinophyma.

Target Phenotypes: rhinophyma HP:0000414

Show evidence (2 references)

PMID:41918801 SUPPORT Human Clinical

"we emphasize the surgical value of local anesthesia with CO2 laser for rhinophyma, reducing blood loss, operation time, and the need for secondary surgery."

This case report supports CO2 laser debulking as an effective rhinophyma procedure with practical operative advantages.

PMID:40791837 SUPPORT Human Clinical

"The use of blue laser to treat rhinophyma has shown to be an effective and safe procedure with very promising results."

This provides additional support for laser-based debulking in rhinophyma.

Excisional reconstruction for advanced rhinophyma

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Severe rhinophyma may require excision with reconstructive approaches such as graft-based resurfacing when tissue overgrowth is extensive.

Target Phenotypes: rhinophyma HP:0000414

Show evidence (1 reference)

PMID:40860281 SUPPORT Human Clinical

"Surgical excision is the primary treatment, and various techniques are available."

This supports excisional surgery as the primary treatment framework for advanced rhinophyma, including graft-based reconstruction.

🌍

Environmental Factors

Ultraviolet B radiation

Ultraviolet B exposure is a recognized favoring factor that can worsen rosacea activity and amplify inflammatory and vascular responses.

Show evidence (1 reference)

PMID:34035646 SUPPORT Human Clinical

"Microorganisms, genetic predisposition, corticosteroid treatment, and ultraviolet B (UVB) radiation are favoring factors."

This review explicitly identifies UVB radiation as an important rosacea-promoting exposure.

Mechanism Target:

EXACERBATES Skin barrier dysfunction — Ultraviolet B is listed as a favouring factor rather than a cause, consistent with rosacea being a chronic condition that flares rather than one that ultraviolet initiates. It acts on a barrier already compromised.

Show evidence (1 reference)

PMID:34035646 SUPPORT Human Clinical

"Microorganisms, genetic predisposition, corticosteroid treatment, and ultraviolet B (UVB) radiation are favoring factors."

Names ultraviolet B radiation among the favouring factors for this disease, a contributory rather than initiating role.

Corticosteroid treatment

Corticosteroid exposure can favor rosacea expression and is a recognized exacerbating factor in susceptible patients.

Show evidence (1 reference)

PMID:34035646 SUPPORT Human Clinical

"Microorganisms, genetic predisposition, corticosteroid treatment, and ultraviolet B (UVB) radiation are favoring factors."

This review explicitly identifies corticosteroid treatment as a favoring factor for rosacea.

Mechanism Target:

EXACERBATES Skin barrier dysfunction — An iatrogenic exposure: topical steroids thin the skin and impair barrier function, producing steroid-induced rosacea and a rebound flare on withdrawal. Notable because the drug is sometimes given for the rash it worsens.

Show evidence (1 reference)

PMID:34035646 SUPPORT Human Clinical

"Microorganisms, genetic predisposition, corticosteroid treatment, and ultraviolet B (UVB) radiation are favoring factors."

Names corticosteroid treatment among the favouring factors for this disease, an iatrogenic contributor.

📊

Prevalence

Worldwide general population (pooled, 41 populations)

Point Prevalence 5460.0 per 100,000 (4910.0–6040.0) >1 in 1,000

Proportion meta-analysis of 32 studies (26,519,836 individuals; 22 of 41 populations European). Pooled 5.46% (95% CI 4.91-6.04); women 5.41%, men 3.90%, peak at ages 45-60. Estimates are method-dependent: higher in symptom questionnaires, lower in ICD-coded registries.

Show evidence (2 references)

PMID:29478264 SUPPORT Human Clinical

"The pooled proportion of individuals with rosacea was 5·46% [95% confidence interval (CI) 4·91-6·04] in the general population and 2·39% (95% CI 1·56-3·39) among dermatological outpatients."

Pooled general-population point prevalence from the meta-analysis.

PMID:29478264 SUPPORT Human Clinical

"Self-reported rosacea gave higher prevalence estimates than rosacea diagnosed by clinical examination, suggesting a low specificity of questionnaires based on symptoms."

Documents the ascertainment dependence behind the wide range of published estimates.

Dermatological outpatients (pooled)

Point Prevalence 2390.0 per 100,000 (1560.0–3390.0) >1 in 1,000

Same meta-analysis; proportion of dermatology outpatient attendances with rosacea (2.39%, 95% CI 1.56-3.39), a clinic-based rather than population denominator.

Show evidence (1 reference)

PMID:29478264 SUPPORT Human Clinical

"The pooled proportion of individuals with rosacea was 5·46% [95% confidence interval (CI) 4·91-6·04] in the general population and 2·39% (95% CI 1·56-3·39) among dermatological outpatients."

Pooled outpatient-clinic prevalence from the same meta-analysis.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Rosacea:

Acne MONDO:0011438

Overlapping Features Acne can overlap clinically with papulopustular rosacea because both produce inflammatory papules and pustules on the face.

Distinguishing Features

Acne more often shows open or closed comedones and broader sebaceous facial or truncal involvement.
Rosacea more often centers on persistent centrofacial erythema, flushing, and telangiectasia without comedones.

Show evidence (1 reference)

PMID:11582639 SUPPORT Human Clinical

"It can be difficult to distinguish acne vulgaris, seborrheic eczema, perioral dermatitis and lupus erythematosus from rosacea."

This review explicitly lists acne vulgaris among the core differential diagnoses for rosacea.

Seborrheic dermatitis MONDO:0006608

Overlapping Features Facial seborrheic dermatitis can mimic rosacea when patients present with chronic erythema in sebaceous facial regions.

Distinguishing Features

Seborrheic dermatitis more often has greasy yellow-white scale involving the eyebrows, nasolabial folds, and scalp.
Rosacea more often has flushing, telangiectasia, and papulopustular lesions without prominent greasy scale.

Show evidence (1 reference)

PMID:11582639 SUPPORT Human Clinical

"It can be difficult to distinguish acne vulgaris, seborrheic eczema, perioral dermatitis and lupus erythematosus from rosacea."

This review explicitly identifies seborrheic eczema as a major rosacea mimic; the corresponding MONDO disease term used here is seborrheic dermatitis.

Lupus erythematosus Not Yet Curated MONDO:0004670

Overlapping Features Lupus erythematosus can resemble rosacea when facial erythema or a butterfly-pattern eruption predominates.

Distinguishing Features

Lupus erythematosus more often has photosensitivity, scale, dyspigmentation, scarring plaques, or systemic autoimmune features.
Rosacea more often has trigger-provoked flushing, telangiectasia, and papulopustular centrofacial inflammation.

Show evidence (2 references)

PMID:11582639 SUPPORT Human Clinical

"It can be difficult to distinguish acne vulgaris, seborrheic eczema, perioral dermatitis and lupus erythematosus from rosacea."

This review explicitly lists lupus erythematosus among disorders that can be difficult to distinguish from rosacea.

PMID:41695827 SUPPORT Human Clinical

"The coexistence of rosacea and lupus-like lesions delayed diagnosis, highlighting the need for clinicopathological correlation."

This case report reinforces lupus erythematosus as a real-world rosacea mimic and overlap diagnosis.

Systemic sclerosis MONDO:0005100

Overlapping Features Rosacea-associated solid facial edema can mimic systemic sclerosis when facial induration or swelling dominates the presentation.

Distinguishing Features

Systemic sclerosis more often has Raynaud phenomenon, acral involvement, and broader connective-tissue disease manifestations.
Morbihan-type rosacea edema may remain centered on the face with sparing of the hands and feet.

Show evidence (1 reference)

PMID:41694889 SUPPORT Human Clinical

"Scleredema diabeticorum and Morbihan disease (solid facial edema) can mimic scleroderma, creating diagnostic challenges for rheumatologists."

This directly supports systemic sclerosis-spectrum disease as a differential diagnosis for edematous rosacea presentations.

Coccidioidomycosis MONDO:0005706

Overlapping Features Cutaneous coccidioidomycosis can mimic rosacea-like dermatitis, particularly in immunocompromised patients living in endemic regions.

Distinguishing Features

Coccidioidomycosis is favored by endemic exposure, immunosuppression, and biopsy evidence of fungal infection.
Rosacea lacks an infectious tissue diagnosis and more typically follows a chronic trigger-responsive vascular-inflammatory course.

Show evidence (1 reference)

PMID:41017054 SUPPORT Human Clinical

"An immunocompromised patient in Arizona, USA, experienced cutaneous coccidioidomycosis mimicking rosacea-like dermatitis"

This directly documents cutaneous coccidioidomycosis as a rosacea mimic in the appropriate epidemiologic context.

Lymphomatoid papulosis Not Yet Curated MONDO:0020326

Overlapping Features Recurrent periocular nodules can be misclassified as papulopustular rosacea before biopsy reveals a CD30-positive lymphoproliferative lesion.

Distinguishing Features

Lymphomatoid papulosis shows recurrent papulonodules with diagnostic CD30-positive atypical lymphoid infiltrates on histopathology.
Rosacea more typically produces diffuse erythema, papules, pustules, and telangiectasia rather than isolated recurrent nodules.

Show evidence (1 reference)

PMID:40827152 SUPPORT Human Clinical

"he was subsequently diagnosed with papulopustular rosacea and impetigo. However, despite multiple treatment trials, he still experienced recurrent flares with nodules"

This case report documents an initial rosacea diagnosis later revised to lymphomatoid papulosis after biopsy.

📊

Related Datasets

Th1/Th17 Immune Response in Rosacea geo:GSE65914

Human facial biopsy transcriptomic dataset spanning rosacea subtypes and healthy controls, used to define adaptive immune and inflammatory cell programs across erythematotelangiectatic, papulopustular, and phymatous disease.

human MICROARRAY n=58

Conditions: erythematotelangiectatic rosacea papulopustular rosacea phymatous rosacea healthy control facial skin

PMID:25848978

Show evidence (1 reference)

GEO:GSE65914 SUPPORT Human Clinical

"The T cell response is dominated by Th1/Th17-polarized immune cells, as demonstrated by significant upregulation of IFNγ or IL-17, for example."

This GEO series directly supports subtype-spanning adaptive immune polarization in human rosacea tissue.

Paired transcriptomic and proteomic analysis implicates IL-1β in the pathogenesis of papulopustular rosacea explants [RNA-seq] geo:GSE155141

Human RNA-seq dataset from paired non-lesional and lesional papulopustular rosacea explants, linked to paired proteomic profiling and inflammatory pathway analysis.

human BULK RNA SEQ n=15

Conditions: non-lesional papulopustular rosacea skin lesional papulopustular rosacea skin IL-1beta-treated non-lesional rosacea skin

PMID:32941918

Show evidence (1 reference)

GEO:GSE155141 SUPPORT In Vitro

"Our study suggests that MAPK and TNF signaling pathways are the most significantly upregulated pathways in lesional papulopustular rosacea human skins, highlighting IL-1β as a potential central mediator."

This dataset captures lesion-associated inflammatory pathway activity in papulopustular rosacea. Graded IN_VITRO because the profiled material is cultured ex vivo biopsy explants, which this repository classes as in vitro, matching the sibling in vitro keratinocyte dataset geo:GSE303282.

Cathelicidin LL-37-induced transcriptome of human keratinocyte identifies chemokine CXCL10 link to T cell-mediated rosacea pathogenesis via JAK-1/STAT-1 pathway geo:GSE303282

Human keratinocyte microarray dataset modeling LL-37-driven rosacea-like inflammation in vitro to resolve chemokine and JAK-STAT signaling outputs downstream of cathelicidin exposure.

human MICROARRAY n=6

Conditions: LL-37-treated primary keratinocytes untreated primary keratinocytes

Show evidence (1 reference)

GEO:GSE303282 SUPPORT In Vitro

"Mechanistically, LL-37 induced CXCL10 production relied on JAK-1/STAT-1 signaling pathway."

This in vitro transcriptomic dataset is directly relevant to the cathelicidin and STAT-linked mechanism nodes in rosacea.

Effect of eyelid UVB irradiation on gene expression of rat meibomian gland geo:GSE277020

Rat bulk RNA-seq dataset from a UVB-induced ocular rosacea model focused on meibomian gland dysfunction, ocular surface injury, and downstream inflammatory and keratinization pathways.

Rattus norvegicus BULK RNA SEQ n=7

Conditions: UVB-irradiated rat eyelids and meibomian glands non-irradiated rat controls

Show evidence (1 reference)

GEO:GSE277020 SUPPORT Model Organism

"We have developed a rat model of UVB-induced ocular surface and eyelid damages mimicking ocular rosacea, a common chronic inflammatory and neurovascular ocular surface disease associated with meibomian gland dysfunction."

This dataset provides an ocular/meibomian model aligned to the ocular rosacea subgraph in this entry.

A positive feedback circuit between mTORC1 signaling and cathelicidin promotes skin inflammation in rosacea [mouse] geo:GSE147950

Mouse bulk RNA-seq from an LL-37-induced rosacea-like skin model, with and without rapamycin, used to define the mTORC1-cathelicidin positive feedback loop that amplifies cutaneous inflammation. Aligns with the cathelicidin/LL-37 arm of the pathograph.

mouse BULK RNA SEQ n=12

Conditions: rosacea-like mouse skin lesions control mouse skin rapamycin-treated skin

PMID:33734592

Show evidence (1 reference)

GEO:GSE147950 SUPPORT Model Organism

"The goal of this study is to figure out the role of mTORC1 signaling in the pathogenesis of rosacea by comparing rosacea mouse model skin lesion transcriptome profiling (RNA-seq) to that of control mouse skin treated with or without rapamycin."

GEO summary establishes this as a rosacea mouse-model transcriptome designed to interrogate mTORC1 signaling, a regulator upstream of the cathelicidin pathway modeled in this entry.

Dorsal Root Ganglion-Mediated Modulation of Neuroinflammation and Neurovasodilation in Rosacea by Gabapentin geo:GSE308876

Mouse bulk RNA-seq of skin and dorsal root ganglia from an LL-37-induced rosacea model treated with gabapentin, profiling neuroimmune and neurovascular activation (CGRP, nitric oxide synthases) and its suppression. Aligns with the TRP/neuropeptide and neurovascular vasodilation nodes.

mouse BULK RNA SEQ n=24

Conditions: LL-37-induced rosacea-like mouse skin LL-37-induced rosacea-like mouse dorsal root ganglia gabapentin-treated skin and dorsal root ganglia

No linked publication is listed on the GEO record at time of curation.

Show evidence (1 reference)

GEO:GSE308876 SUPPORT Model Organism

"LL37 triggered parallel neuroimmune and neurovascular activation in skin and DRG, including upregulating of Th2, IGF, CGRP, and nitric oxide synthases."

GEO summary documents neuropeptide (CGRP) and nitric oxide synthase induction in the LL-37 rosacea model, the neurovascular program this entry models.

RNAseq of Mineralocorticoid Receptor (MR) overexpression in UVB-induced ocular rosacea model on meibomian glands of rats geo:GSE291177

Rat meibomian-gland bulk RNA-seq from the UVB-induced ocular rosacea model, comparing wild-type animals with rats overexpressing the human mineralocorticoid receptor. Companion to GSE277020 from the same model and aligned to the meibomian gland dysfunction node.

Rattus norvegicus BULK RNA SEQ n=17

Conditions: UVB-irradiated wild-type rat meibomian glands UVB-irradiated mineralocorticoid-receptor-overexpressing rat meibomian glands non-irradiated wild-type and transgenic controls

No linked publication is listed on the GEO record at time of curation.

Show evidence (1 reference)

GEO:GSE291177 SUPPORT Model Organism

"The aim of this study was to analyse the transcriptional regulation of UVB-induced ocular rosacea model on the meibomian glands of rats that overexpress the human NRC32 gene coding for mineralocorticoid receptor (P1.hMR) and age- and sex- matched wild type (WT) littlemates."

GEO summary identifies this as a meibomian-gland transcriptome from the UVB ocular rosacea model, matching the ocular subgraph.

Agonism of the glutamate receptor GluK2 suppresses dermal mast cell activation and cutaneous inflammation geo:GSE268986

Mouse mast-cell transcriptomic dataset from a study of GluK2 agonism (SYM2081) as a suppressor of MrgprB2-driven mast cell activation, with in vivo validation in murine dermatitis and rosacea models. Aligns with the mast cell-mediated amplification node; rosacea is one of two disease models in the study, not its sole focus.

mouse BULK RNA SEQ n=12

Conditions: SYM2081-treated mast cells vehicle-treated mast cells

PMID:39661706

Show evidence (1 reference)

GEO:GSE268986 SUPPORT Model Organism

"Finally, pretreatment with SYM2081 significantly reduced skin inflammation in murine dermatitis and rosacea models."

GEO summary reports rosacea-model validation of mast-cell-targeted suppression, relevant to the mast cell amplification step in this entry.

Innate type 2 immunity controls hair follicle commensalism by Demodex mites [2019] geo:GSE197981

Mouse hair-follicle bulk RNA-seq from a study showing that ILC2-derived IL-13 restrains Demodex outgrowth; loss of this checkpoint drives inflammatory follicular programs and barrier loss. The study links its mouse findings to human rhinophymatous rosacea. Aligns with the Demodex Folliculorum Proliferation node.

mouse BULK RNA SEQ n=6

Conditions: Demodex-colonized mouse hair follicles ILC2/IL-13-deficient Demodex-colonized hair follicles

PMID:36044899

Two small (n=4) sibling sub-series from the same study, GSE198657 and GSE197982, exist in GEO; only the primary series is recorded here.

Show evidence (1 reference)

GEO:GSE197981 SUPPORT Model Organism

"Humans with rhinophymatous acne rosacea, a nasal inflammatory condition associated with a high burden of Demodex, had increased HF inflammatory cells with decreased type 2 cytokines, consistent with the inverse relationship seen in mice."

GEO summary ties the mouse Demodex-commensalism transcriptome to the high mite burden of human phymatous rosacea, supporting the Demodex proliferation mechanism in this entry.

Million Veteran Program (MVP) rosacea genome-wide association summary statistics dbgap:phs001672

Genome-wide association summary statistics for rosacea (PheCode 695.3) from the VA Million Veteran Program phenome-wide atlas, the only public rosacea GWAS with deposited full summary statistics. European-ancestry analysis of 14,815 cases and 427,372 controls; access to individual level data is governed by dbGaP. The phenotype is an EHR PheCode, not a dermatologist-confirmed cohort.

human GWAS n=442187

Conditions: rosacea (PheCode 695.3), European ancestry rosacea (PheCode 695.3), African American or Afro-Caribbean ancestry rosacea (PheCode 695.3), Hispanic or Latin American ancestry

PMID:39024449

No evidence block: the publication is a 2,068-trait atlas whose text does not name rosacea, so nothing in it can be quoted for this record. Trait-level results are catalogued by the GWAS Catalog, which has no reference prefix in this repository, so they are recorded here as provenance. GCST90476178 (European ancestry) lists eight genome-wide significant associations: rs6866614 (IRF1/CARINH), rs12203592 (IRF4), rs12898729 (HERC2), rs5743618 (TLR1), rs10806180 (near ELOVL4), and three signals given only as positions (chr2:28627629, chr7:50327367, chr16:90024970). The IRF4 and HERC2 hits replicate the 23andMe symptom-severity loci recorded in the genetic section, and the IRF1 hit independently corroborates the Mendelian-randomization-derived IRF1 entry. The TLR1 signal is mechanistically notable given the TLR2 pathway in this entry, since TLR1 heterodimerizes with TLR2. The African-ancestry analysis (GCST90480451, 410 cases) reports nine associations dominated by pigmentation variants (rs16891982 SLC45A2, rs1805007 MC1R, rs12203592, rs12898729); with so few cases in an admixed sample these are more plausibly ancestry stratification than replication and are not curated as gene entries. The Hispanic-ancestry analysis (GCST90478792) reports no genome-wide significant hits.

Distinct diversity of skin cell populations of rhinophyma and hypertrophic scar illustrated by scRNA-seq arrayexpress:E-MTAB-16629

10x Chromium single-cell RNA-seq of surgically resected rhinophyma (phymatous rosacea of the nose) compared with hypertrophic scar and healthy skin, designed to explain why rhinophyma tissue reverts toward normal after surgical debulking whereas hypertrophic scar recurs. The only single-cell dataset of end-stage phymatous disease; aligns with the sebaceous gland and soft tissue hyperplasia/fibrosis node.

human SINGLE CELL RNA SEQ n=3

Conditions: rhinophyma hypertrophic scar healthy skin

Released 2026-02-18 (BioStudies; 11 files). The repository lists three disease groups and no linked publication at time of curation; sample count is the repository's own figure. ArrayExpress records are resolved against the BioStudies API on each verifier run and are not cached, so this record carries no quoted evidence.

Skin microbiome characterization in rosacea patients and healthy controls bioproject:PRJEB37562

Facial skin bacterial and fungal microbiome profiling in rosacea patients versus healthy controls. The project description reports subtype-specific shifts: increased Staphylococcus in erythematotelangiectatic and increased Streptococcus in papulopustular rosacea. The one cutaneous dysbiosis dataset stratified by clinical subtype.

human

skin of face UBERON:1000021

Conditions: erythematotelangiectatic rosacea facial skin papulopustular rosacea facial skin healthy control facial skin

ENA holds this accession as a study record only: no run, sample or analysis objects are linked under it at time of curation, so the read data are not retrievable from the accession. The project registration (2020-06-26) and description match Woo et al. 2020, Br J Dermatol, PMID:32533846 ("Bacterial and fungal microbiome characterization in patients with rosacea and healthy controls"), but the repository lists no publication link, so the PMID is recorded here rather than in publication. No data_type is set because the schema enum has no value for amplicon (16S/ITS) metagenomics.

Multi-omics study of microbe-host interactions in rosacea bioproject:PRJEB82826

Cutaneous microbiome (96 amplicon runs in ENA) with paired Demodex density and host skin transcriptome from rosacea patients before and after 30 days of topical 1% ivermectin, versus healthy volunteers. The dataset that separates the mite, microbiome and host-transcriptome arms of the Demodex mechanism: ivermectin cleared mites and normalized the host transcriptome without correcting bacterial dysbiosis.

human MULTI OMICS n=96

skin of face UBERON:1000021

Conditions: rosacea lesional skin, day 0 (pre-ivermectin) rosacea lesional skin, day 30 (post-ivermectin) healthy volunteer skin

PMID:40220854

Sample count is the number of amplicon read runs in ENA; a sibling umbrella accession, PRJEB82848, carries the same title and description but no data objects and is not recorded separately. The host transcriptome arm is not among the ENA runs under this accession.

Show evidence (2 references)

PMID:40220854 SUPPORT Human Clinical

"At day 0, distinct microbial community changes included the decrease in Cutibacterium acnes abundance, whereas Staphylococcus epidermidis colonization increased compared with that in healthy volunteers."

The cutaneous dysbiosis signature measured in this dataset.

PMID:40220854 SUPPORT Human Clinical

"However, improvement of clinical signs during topical ivermectin is not associated with normalization of the bacterial microbiome but rather a decrease of transcriptomic dysregulation and mite density."

Dissociates the treatment response from bacterial dysbiosis and ties it to mite clearance and host transcriptome normalization, the Demodex-directed reading of the acaricide link in this entry.

Topical ivermectin treatment of rosacea changes the bacterial microbiome of the skin bioproject:PRJDB18292

16S bacterial microbiome of facial skin in rosacea patients sampled before and after topical ivermectin treatment (24 SRA experiments, DDBJ). A second, independent pre/post-ivermectin microbiome design complementing PRJEB82826.

human n=24

skin of face UBERON:1000021

Conditions: rosacea facial skin, pre-ivermectin rosacea facial skin, post-ivermectin

PMID:39481532

Publication is the same-titled 2025 J Invest Dermatol paper; its abstract could not be retrieved into the reference cache, so no quoted evidence is attached. No data_type is set because the schema enum has no value for amplicon (16S) metagenomics.

Skin, blood, stool microbiome in rosacea bioproject:PRJNA1189573

16S rRNA bacterial microbiome profiled simultaneously in skin, blood and stool from rosacea patients and controls (93 SRA experiments): a multi-site design that directly tests the gut-skin axis rather than inferring it from cutaneous data alone.

human n=93

skin of face UBERON:1000021 blood UBERON:0000178 feces UBERON:0001988

Conditions: rosacea patients (skin, blood, stool) control participants (skin, blood, stool)

Sample count is the number of SRA experiments. No linked publication on the record at time of curation; no data_type is set because the schema enum has no value for amplicon (16S) metagenomics.

Skin, blood, stool mycobiome in rosacea bioproject:PRJNA1288008

Fungal (ITS) mycobiome companion to PRJNA1189573, profiling skin, blood and stool from rosacea patients and controls (66 SRA experiments), so that fungal dysbiosis can be assessed alongside the bacterial data across the same body sites.

human n=66

skin of face UBERON:1000021 blood UBERON:0000178 feces UBERON:0001988

Conditions: rosacea patients (skin, blood, stool) control participants (skin, blood, stool)

Sample count is the number of SRA experiments. No linked publication on the record at time of curation; no data_type is set because the schema enum has no value for amplicon (ITS) metagenomics.

Raw 16S rRNA Sequencing Data of Fecal Samples from Patients with Neurogenic Rosacea bioproject:PRJNA1191396

Fecal 16S rRNA microbiome from patients with neurogenic rosacea (34 SRA experiments), the burning/stinging-predominant presentation, probing the gut-skin-nerve axis behind the TRP and neuropeptide signaling node.

human n=34

feces UBERON:0001988

Conditions: neurogenic rosacea fecal samples

Sample count is the number of SRA experiments. The record does not say whether controls are included. No linked publication on the record at time of curation; no data_type is set because the schema enum has no value for amplicon (16S) metagenomics.

🔬

Clinical Trials

NCT01493947 PHASE_III COMPLETED

Phase III comparative topical trial of ivermectin 1% cream versus metronidazole 0.75% cream in papulopustular rosacea, with an extension period assessing relapse-related outcomes.

Target Phenotypes: erythematous papule HP:0030350 pustule HP:0200039

Show evidence (1 reference)

clinicaltrials:NCT01493947 SUPPORT Human Clinical

"To compare efficacy and safety of Ivermectin 1% cream versus metronidazole 0.75% cream in subjects with papulopustular rosacea after 16-week topical treatment."

This registry summary supports a pivotal interventional trial focused on papulopustular rosacea lesion control.

NCT00126399 PHASE_III COMPLETED

Phase III placebo-controlled trial of once-daily 40 mg doxycycline controlled-release capsules for rosacea.

Target Phenotypes: erythematous papule HP:0030350 pustule HP:0200039

Show evidence (1 reference)

clinicaltrials:NCT00126399 SUPPORT Human Clinical

"The objective of this study is to evaluate the safety and efficacy of 40 mg doxycycline controlled-release capsules administered once daily for the treatment of rosacea compared with a placebo."

This registry entry supports controlled clinical evaluation of subantimicrobial-dose doxycycline for rosacea.

NCT03380390 PHASE_IV COMPLETED

Phase IV open-label study of oxymetazoline 1.0% cream used adjunctively with energy-based therapy for persistent facial erythema in rosacea.

Target Phenotypes: persistent centrofacial erythema HP:0001041

Show evidence (1 reference)

clinicaltrials:NCT03380390 SUPPORT Human Clinical

"This study will evaluate the safety and tolerability of oxymetazoline HCl cream 1.0% when used as an adjunctive treatment to energy-based therapy for participants with moderate to severe persistent facial erythema associated with rosacea."

This trial directly targets the persistent erythema phenotype that anchors erythematotelangiectatic rosacea.

NCT05616923 PHASE_I COMPLETED

Early-phase vehicle-controlled trial evaluating topical MEK inhibition in erythematotelangiectatic rosacea.

Target Phenotypes: persistent centrofacial erythema HP:0001041 flushing HP:0031284

Show evidence (1 reference)

clinicaltrials:NCT05616923 SUPPORT Human Clinical

"This is a prospective, vehicle controlled, double blinded study to evaluate the safety and potential efficacy of a topical formulation of a MEK inhibitor in patients with erythematotelangiectatic rosacea"

This registry entry supports a mechanism-oriented interventional study in the vascular erythematotelangiectatic phenotype.

🧫

Experimental Models

Paired lesional and non-lesional papulopustular rosacea skin explants OTHER

Ex vivo full-thickness facial skin explants taken as paired lesional and non-lesional biopsies from papulopustular rosacea patients, cultured with or without IL-1beta and profiled by RNA-seq and by two proteomic platforms (dataset geo:GSE155141 in this entry). The explant keeps the resident multicellular circuit intact (keratinocytes, fibroblasts, mast cells, vessels and infiltrating immune cells), so it is the one human system that contains the fibroblast-centred network described by single-cell profiling, and the paired design controls for donor. The only NAM here that is human facial skin.

Organism

human NCBITaxon:9606

Tissue

facial skin explant UBERON:1000021

Culture

Ex vivo explant culture of paired human biopsies, untreated or stimulated with recombinant IL-1beta; transcriptome by Illumina RNA-seq in duplicate, proteome by MSD and Olink panels.

Pathograph links

Papulopustular inflammation recapitulates fidelity: high Lesional explants carry the in vivo papulopustular inflammatory program into culture; MAPK and TNF signaling are the most up-regulated pathways versus paired non-lesional tissue.

Limitations: Explants survive days, not the chronic relapsing course; there is no perfusion, no recruitment of circulating leukocytes and no sensory innervation, so the tissue reports the established lesion rather than its initiation or its neurovascular symptoms.

Readouts

Lesional versus non-lesional pathway enrichment (MAPK, TNF)

Direction: INCREASED

Interpretation: Transcriptomic and proteomic pathway activity of the lesion, measured against the same donor's uninvolved skin.

Show evidence (1 reference)

GEO:GSE155141 SUPPORT In Vitro

Reports the pathway readout measured in the explant system.

Show evidence (1 reference)

GEO:GSE155141 SUPPORT In Vitro

"The goal of this study is to utilize human papulopustular rosacea biopsy explants to integrate both differentially expressed genes and differently expressed proteins in paired non-lesional and lesional papulopustular rosacea tissues."

Defines the explant system and its paired lesional design.

NLRP3 Inflammasome Activation perturbs fidelity: moderate Exogenous IL-1beta applied to non-lesional explants perturbs the IL-1 arm downstream of the inflammasome; the dataset-analysis run on this series found IL-1beta induces NLRP3 transcription in non-lesional tissue while the inflammasome module is not elevated at steady state in lesional explants.

Limitations: IL-1beta is the inflammasome's product, not its trigger, so the perturbation tests feed-forward priming rather than LL-37-driven inflammasome assembly; five donor pairs limit power, and the priming effect did not survive FDR correction.

Readouts

NLRP3 transcript after IL-1beta treatment of non-lesional explants

Direction: INCREASED

Interpretation: Feed-forward priming of NLRP3 by IL-1beta in human skin; nominal paired p = 0.025 in the KB's own re-analysis, see notes.

Show evidence (1 reference)

GEO:GSE155141 SUPPORT INDIRECT In Vitro

The series' own conclusion places IL-1beta centrally; the link to the inflammasome node is by inference from the IL-1beta arm.

The NLRP3 readout comes from the assessed dataset-analysis run in kb/hypotheses/Rosacea/ll37_nlrp3_il1b_papulopustular/, not from a publication; no PubMed record is linked to GSE155141 at time of curation, so the GEO summary is the citable source.

SZ95 sebocyte and live Demodex mite co-culture CO_CULTURE

Immortalized human SZ95 sebocytes co-cultured with live Demodex mites extracted from normal facial skin, or exposed to mite-conditioned medium, in time- and mite-dose-dependent experiments with Toll-like receptor pathway gene and protein readouts. The only system in which the mite is the applied perturbation against a human sebaceous cell, the compartment where Demodex lives in vivo.

Organism

human NCBITaxon:9606

Culture

Immortalized SZ95 sebocyte line; live mites or mite-conditioned medium; TLR-pathway expression by RT-PCR array and protein assays; cytokine secretion by ELISA over a 48-hour time course.

Publication

PMID:29532463

Pathograph links

Demodex Folliculorum Proliferation perturbs fidelity: moderate Mite number is the controlled input, so the system tests what a rising mite load does to the sebocyte rather than reproducing follicular proliferation itself.

Limitations: Mites came from normal donors and were applied to a monoculture with no follicular architecture, keratinocytes or immune cells; the TLR response was biphasic (early down-modulation, up-regulation after 48 h), so single-time-point readouts can mislead.

Readouts

Interleukin-8 secretion versus mite number

Direction: INCREASED

Interpretation: Mite-load-dependent pro-inflammatory cytokine output from sebocytes; low numbers did not induce it.

Show evidence (1 reference)

PMID:29532463 SUPPORT In Vitro

"High numbers of Demodex induced proinflammatory cytokine secretion, whereas lower numbers did not."

Reports the dose-dependent cytokine readout.

Show evidence (1 reference)

PMID:29532463 SUPPORT In Vitro

"Live Demodex mites were extracted from normal facial skin of control subjects and used in cell stimulation experiments with the immortalized SZ95 sebocyte line."

Defines the model and its mite-as-input design.

TLR2 upregulation partially recapitulates fidelity: moderate Mite-secreted molecules change TLR2 receptor expression in sebocytes, the cell-type-specific counterpart of the keratinocyte TLR2 rise the node describes.

Limitations: Sebocytes, not keratinocytes; the direction of TLR-pathway change reversed between early and 48-hour time points, so this is a modulation rather than a clean sustained up-regulation.

Readouts

TLR2 receptor expression in sebocytes after mite exposure

Direction: ALTERED

Interpretation: Bidirectional, time-dependent change in TLR2 expression driven by secreted mite factors.

Show evidence (1 reference)

PMID:29532463 SUPPORT In Vitro

"Demodex secreted bioactive molecules that affected TLR2 receptor expression by sebocytes."

Reports the TLR2 expression readout.

Show evidence (1 reference)

PMID:29532463 SUPPORT In Vitro

"Mites modulated TLR signalling events on both mRNA and protein levels in SZ95 sebocytes."

Supports the model as informative for TLR-pathway modulation.

Sebaceous gland dysfunction partially recapitulates fidelity: moderate Shows that the sebocyte is an immune-reactive participant that mites can push into cytokine production, one component of sebaceous-unit dysfunction.

Limitations: Immune reactivity only; sebum lipid output, gland morphology and the hyperplastic changes of phyma are not measured.

Show evidence (1 reference)

PMID:29532463 SUPPORT In Vitro

"Mites have the capacity to secrete bioactive molecules that affect the immune reactivity of sebocytes."

Supports sebocyte immune reactivity as the modelled aspect of sebaceous-unit dysfunction.

HaCaT keratinocytes under simulated rosacea conditions CELL_LINE

Immortalized human HaCaT keratinocytes exposed to conditions simulating the rosacea inflammatory milieu, read out by RT-qPCR, western blot, ELISA and scratch and Transwell assays. Used to test whether the inflammatory gene program seen in patient transcriptomes is reproducible in keratinocytes and to screen candidate drugs. The publication describes the stimulus only as simulated rosacea conditions, so no specific trigger is asserted here.

Organism

human NCBITaxon:9606

Culture

Immortalized HaCaT keratinocyte monolayer; gene and protein expression by RT-qPCR, western blot and ELISA; proliferation and migration by scratch and Transwell assays.

Publication

PMID:39823143

Pathograph links

TLR2 upregulation recapitulates fidelity: moderate Keratinocyte TLR2 and S100A9 protein rise under the simulated rosacea milieu, matching the lesional TLR2 increase in patient skin.

Limitations: An immortalized, spontaneously transformed keratinocyte line in monoculture with no barrier stratification, sebaceous or immune component; the stimulus is not characterized in the abstract.

Readouts

TLR2 and S100A9 protein expression

Direction: INCREASED

Interpretation: Protein-level induction of the innate receptor and its alarmin partner in stimulated keratinocytes.

Show evidence (1 reference)

PMID:39823143 SUPPORT In Vitro

"Specifically, Toll-like receptor 2 (TLR2) and S100A9 proteins were upregulated, potentially promoting these processes."

Reports the TLR2/S100A9 protein readout.

Show evidence (1 reference)

PMID:39823143 SUPPORT In Vitro

"In vitro, HaCaT cells exhibited enhanced proliferation and migration abilities, accompanied by increased expression of pro-inflammatory genes and proteins."

Supports the keratinocyte model as reproducing the inflammatory program in which TLR2 rises.

🐁

Animal Models

LL-37 intradermal injection mouse model

Repeated intradermal injection of the rosacea-associated cathelicidin fragment LL-37 into mouse dorsal skin, introduced by Yamasaki et al. (2007) alongside SCTE/KLK5 addition and Spink5 deletion, reproduces erythema, leukocyte infiltration and epidermal/dermal thickening. Prolonged (20-day) twice-daily administration adds dermal collagen deposition with alpha-SMA, TNF-alpha, vimentin and COL1 induction, and lesions that do not fully recover. It is the standard induced model for TLR/LL-37, mast cell, mTORC1, NLRP3 and neurovascular studies; datasets geo:GSE147950 and geo:GSE308876 in this entry derive from it.

Species

Mouse

Genotype

Wild type (induced model)

Background

BALB/c

Publication

PMID:17676051

Pathograph links

LL-37 generation perturbs fidelity: moderate Exogenous LL-37 substitutes for endogenous KLK5-mediated cathelicidin processing, so the model enters the pathway at the LL-37 step rather than recapitulating its generation.

Limitations: Bypasses upstream initiation (barrier injury, TLR2 induction, KLK5 processing); uses supraphysiological bolus dosing; dorsal murine skin lacks the sebaceous density and facial neurovascular anatomy of human centrofacial skin; no spontaneous relapse.

Show evidence (1 reference)

PMID:17676051 SUPPORT Model Organism

"In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin."

Establishes that supplying the rosacea LL-37 peptides is sufficient to drive the downstream inflammation the node feeds.

Immune cell infiltration recapitulates fidelity: moderate Dermal inflammatory-cell aggregation with epidermal and dermal thickening after repeated LL-37 injection.

Limitations: Infiltrate composition in mouse dorsal skin has not been shown to match the Th1/Th17, mast cell and macrophage/dendritic profile of human lesions.

Readouts

Dermal inflammatory cell aggregation on H&E

Direction: INCREASED

Interpretation: Histological correlate of the immune infiltration node in this model.

Show evidence (1 reference)

PMID:37185701 SUPPORT Model Organism

"Haematoxylin and eosin (H&E) and Van Gieson's staining showed a high degree of inflammatory cell aggregation, thickening of the epidermis and dermis, and collagen deposition in large quantities."

Reports the histological measurement behind this readout.

Show evidence (1 reference)

PMID:37185701 SUPPORT Model Organism

"Haematoxylin and eosin (H&E) and Van Gieson's staining showed a high degree of inflammatory cell aggregation, thickening of the epidermis and dermis, and collagen deposition in large quantities."

Supports treating the model as informative for lesional immune infiltration.

Fibrotic dermal remodeling partially recapitulates fidelity: low Prolonged LL-37 dosing produces dermal collagen deposition with alpha-SMA and COL1 induction that persists after injections stop.

Limitations: Collagen deposition appears only with long-term dosing and is diffuse dorsal-skin fibrosis, not the sebaceous and soft-tissue hyperplasia of phymatous nasal disease; short-term dosing produces no fibrosis and fully recovers.

Readouts

Dermal collagen deposition with alpha-SMA and COL1 induction

Direction: INCREASED

Interpretation: Van Gieson collagen staining plus immunofluorescence/Western blot for myofibroblast and collagen markers.

Show evidence (1 reference)

PMID:37185701 SUPPORT Model Organism

"The results of immunofluorescence staining and Western blotting showed that the expression of α-SMA, TNF-α, vimentin, and COL1 in the skin of mice was significantly upregulated."

Reports the marker measurements behind this readout.

Show evidence (1 reference)

PMID:37185701 SUPPORT Model Organism

"However, rosacea-like skin lesions induced by long-term LL-37 administration did not completely recover."

Persistence after withdrawal is what makes the model informative for irreversible remodeling rather than transient inflammation.

Angiogenic vascular remodeling recapitulates fidelity: moderate Long-term LL-37 induction produces dermal angiogenesis alongside skin thickening.

Limitations: Reported as a histological feature of the long-term protocol; the short-term protocol does not develop it.

Show evidence (1 reference)

PMID:40296272 SUPPORT Model Organism

"Mice subjected to long-term LL-37 induction developed rosacea-like pathological features, including angiogenesis, thickened skin tissue, and sebaceous gland hypertrophy."

Angiogenesis is among the long-term model's defining features.

Sebaceous gland and soft tissue hyperplasia/fibrosis partially recapitulates fidelity: low Long-term LL-37 induction produces sebaceous gland hypertrophy with dermal thickening, the earliest tissue-level analogue of phymatous change.

Limitations: Dorsal murine sebaceous hypertrophy is not nasal rhinophyma; the model lacks the human nose's sebaceous density and the decades-long course over which phyma develops.

Show evidence (1 reference)

PMID:40296272 SUPPORT Model Organism

"Mice subjected to long-term LL-37 induction developed rosacea-like pathological features, including angiogenesis, thickened skin tissue, and sebaceous gland hypertrophy."

Sebaceous gland hypertrophy appears only with prolonged induction, matching the late position of phymatous change in the pathograph.

Show evidence (2 references)

PMID:17676051 SUPPORT Model Organism

The founding description of LL-37 injection as a rosacea-like inflammation model.

PMID:37185701 SUPPORT Model Organism

"Balb/c mice were continuously injected intradermally with LL-37 every 12 h to induce a rosacea-like phenotype."

Current protocol (strain, route, dosing interval) for the model.

Facial LL-37 injection mouse model with trigeminal readouts

A variant of the LL-37 model in which the peptide is injected intradermally into the face rather than the dorsum, so that lesions form in facial skin innervated by the trigeminal ganglion. Used to study the sensory symptoms of rosacea: facial injection produced rosacea-like lesions together with pruritus-indicative behaviour, and the temperature-sensitive channels TRPV4 and TRPM8 were increased in both the lesional skin and the trigeminal ganglion, matching increases in human rosacea skin. This is the only rodent model in this entry that uses the facial site and its native sensory innervation.

Species

Mouse

Genotype

Wild type (induced model)

Publication

PMID:36517318

Pathograph links

TRP and neuropeptide signaling recapitulates fidelity: moderate Facial LL-37 lesions are accompanied by increased TRPV4 and TRPM8 in skin and in the trigeminal ganglion, with pruritus behaviour, so the model reports the sensory-neuron arm of the neurovascular program at its anatomically correct site.

Limitations: Reports itch-related TRPV4/TRPM8 rather than the TRPV1/TRPA1-CGRP axis usually invoked for flushing and burning; behavioural pruritus scoring in mice is an indirect proxy for human sensory symptoms; mouse facial skin still differs from human centrofacial skin in sebaceous and vascular density.

Readouts

TRPV4 and TRPM8 expression in lesional facial skin and trigeminal ganglion

Direction: INCREASED

Interpretation: Transcript and protein increase of temperature-sensitive TRP channels in the skin and its sensory ganglion, paralleled in human rosacea skin samples.

Show evidence (1 reference)

PMID:36517318 SUPPORT Model Organism

"Increased expression of the temperature-sensitive receptors TRPV4 and TRPM8 was found in pruritic mouse skin and TG and human skin samples."

Reports the measurement behind this readout in both model and human tissue.

Show evidence (1 reference)

PMID:36517318 SUPPORT Model Organism

"Increased expression of the temperature-sensitive receptors TRPV4 and TRPM8 was found in pruritic mouse skin and TG and human skin samples."

Supports treating the facial model as informative for TRP-channel sensory signaling.

Show evidence (2 references)

PMID:36517318 SUPPORT Model Organism

"The LL-37 was injected intradermally into the face of mice to establish the animal model."

Defines the facial-site variant of the LL-37 model.

PMID:36517318 SUPPORT Model Organism

"Intradermal injection of LL-37 not only caused rosacea-like facial lesions but also induced a behavioural pattern indicative of pruritus."

Facial lesions plus a sensory-symptom readout.

Demodex mite injection rabbit model

Intradermal injection of a suspension of Demodex mites into rabbit skin, followed over four weeks. Erythematous papules appear by the second week, with foreign-body material, telangiectasia and then an organized granuloma-like structure on histology, mimicking the lesions and histopathology of Demodex-positive rosacea. The only model in this entry in which the mite itself is the perturbation in vivo.

Species

Rabbit

Genotype

Wild type (induced model)

Background

Japanese rabbit

Publication

PMID:36177392

Pathograph links

Demodex Folliculorum Proliferation perturbs fidelity: low A bolus of injected mites stands in for follicular mite proliferation, so the model perturbs the Demodex node rather than reproducing gradual pilosebaceous colonization.

Limitations: Injected mite suspension bypasses follicular residence and the sebocyte interface where Demodex acts in humans; the resulting foreign-body and granulomatous reaction is a stronger stimulus than commensal overgrowth; rabbit skin is not sebaceous facial skin.

Show evidence (1 reference)

PMID:36177392 SUPPORT Model Organism

"the model of Demodex-induced rosacea-like skin lesions can be developed through intradermal injection of suspension of Demodex mites into Japanese rabbits."

The mite is the applied perturbation.

Papulopustular inflammation partially recapitulates fidelity: low Mite injection produces erythematous papules and telangiectasia with a granuloma-like histology.

Limitations: The lesion is granulomatous around foreign mite material rather than the neutrophilic follicular pustule of human papulopustular rosacea; no pustules are reported.

Readouts

Erythematous papules, telangiectasia and granuloma-like structure on H&E

Direction: INCREASED

Interpretation: Sequential clinical and histological lesion development over four weeks.

Show evidence (1 reference)

PMID:36177392 SUPPORT Model Organism

"Lumpy foreign bodies, telangiectasia and granuloma-like structure were observed in the model rabbit in the 1st, 2nd, and 3rd weeks, respectively."

Reports the histological readouts and their timing.

Show evidence (1 reference)

PMID:36177392 SUPPORT Model Organism

"Erythema papules were observed in the model rabbit skin and could be observed most clearly in the 2nd week."

Supports the model as informative for the papular lesion, with the granulomatous caveat above.

Show evidence (2 references)

PMID:36177392 SUPPORT Model Organism

"the model of Demodex-induced rosacea-like skin lesions can be developed through intradermal injection of suspension of Demodex mites into Japanese rabbits."

Defines the model.

PMID:36177392 SUPPORT Model Organism

"The model can mimic the phenotype of skin lesions and histopathological manifestations in the Demodex mite-positive patient with rosacea."

The authors' statement of what the model reproduces.

🧮

Computational Models

Rosacea Innate-Immune Axis Boolean Model Boolean rule specification (YAML) Python (standard library and PyYAML) BOOLEAN_NETWORK

A synchronous Boolean network of the cutaneous innate-immune arm of rosacea: barrier impairment and Demodex proliferation through pro-cathelicidin transcription, TLR2, KLK5/KLK7 and LL-37 to the inflammasome, mast-cell, Th1/Th17 and angiogenic branches, and on to the vascular and papulopustular phenotypes. Authored in this repository rather than curated from a publication, because no Boolean, logical or other dynamical model of rosacea has been published; PubMed returns nothing for rosacea combined with Boolean network, logical model, agent-based or mathematical model, and the computational rosacea literature is entirely network pharmacology and molecular docking. Every node maps to a pathophysiology, environmental, treatment or phenotype node in this entry, and every rule transcribes causal edges curated here, so the model asserts no biology of its own: it makes the curated chain executable, so that what the chain implies can be derived instead of argued. Nothing in it is fitted to data.

Pathograph links

Papulopustular inflammation partially recapitulates fidelity: low The node is reproduced as the disjunction of its three curated upstream edges, so the model reproduces which arms can produce the lesion but not how much of each is needed, nor its time course.

Limitations: Binary activity with synchronous update: no dose, no kinetics, no threshold behaviour and no partial response. Treating the three upstream edges as independently sufficient is the least safe assumption in the model; if lesion formation actually requires several arms together, the single-agent results are optimistic.

Readouts

Papulopustular_inflammation node state across the intervention scan

Direction: UNCHANGED

Interpretation: The node stays active under every single and paired combination of the three encodable interventions, because none of them acts on the immune-infiltration arm.

Neurovascular vasodilation partially recapitulates fidelity: low Reproduced as the disjunction of its three curated upstream edges (mast-cell amplification, fibroblast expansion, TRP and neuropeptide signaling), gated by topical brimonidine.

Limitations: TRP and neuropeptide signaling is an input rather than a computed node, because the entry curates no upstream cause for it, so the model cannot represent a trigger-driven flush. Brimonidine's target is inferred from its treatment description, since it carries no curated target_mechanisms edge.

Readouts

Flushing node state under brimonidine

Direction: DECREASED

Interpretation: Brimonidine clears the flushing output but leaves persistent erythema active, because erythema is additionally fed by the angiogenic-remodeling branch.

Findings

No combination of the interventions that can be grounded in this entry switches off the papulopustular phenotype in the model.

"Papulopustular inflammation is driven by three curated edges in parallel (inflammasome, immune-cell infiltration, Th1/Th17), and the immune-infiltration arm is fed by barrier dysfunction through STAT3, by fibroblast expansion and by the ACSL5 node. The entry curates exactly one..."

Removing mites alone clears only telangiectasia in the model, which overstates what an acaricide does to the cathelicidin axis.

"Demodex proliferation is the only curated upstream cause of TLR2 upregulation in this entry, so switching it off removes TLR2, KLK5/KLK7 and therefore all of LL-37's branches. Ultraviolet exposure and barrier impairment are curated onto pro-cathelicidin transcription but not onto TLR2, so the..."

The erythematotelangiectatic scenario produces papules and pustules, which is clinically wrong and exposes the absence of subtype gating in the curated graph.

"With mites off but barrier, fibroblast and ACSL5 inputs on, the immune-infiltration arm still fires and the papulopustular node with it. The curated edges carry no subtype conditionality, and the model inherits that: it cannot represent a vascular-predominant phenotype without papulopustular..."

Spec models/rosacea_innate_boolean.yaml, runner models/rosacea_innate_boolean.py, committed results models/rosacea_innate_boolean.results.json. Regenerate with `uv run python models/rosacea_innate_boolean.py`; `--check` fails if the committed results are stale and `--print` shows the summary. The runner is deterministic, uses only the standard library and PyYAML, and parses the rule language rather than calling eval. NOT wired to dismech-perturb and deliberately given no models/rosacea_innate_boolean.config.yaml: that runner executes SBML through tellurium and cannot run a logical network, so the model is correctly reported as not runnable in-repo by the models browser. The spec records, per rule, which curated edges it encodes and which Boolean choices (the AND at LL-37 generation, the ORs elsewhere) the edge list did not itself determine.

{ }

Source YAML

click to show

name: Rosacea
creation_date: "2026-04-05T12:00:00Z"
category: Complex
description: >-
  Rosacea is a chronic relapsing inflammatory facial dermatosis centered on
  persistent or episodic centrofacial erythema, flushing, telangiectasia, and
  papulopustular lesions, with phymatous and ocular involvement in a subset of
  patients. Current mechanistic models emphasize dysregulated innate immunity,
  neurovascular hyperreactivity, skin barrier impairment, and trigger-dependent
  disease amplification.
disease_term:
  preferred_term: rosacea
  term:
    id: MONDO:0006604
    label: rosacea
parents:
- Dermatological Disease
- Inflammatory Skin Disease
has_subtypes:
- name: Erythematotelangiectatic Rosacea
  description: >-
    Predominantly vascular rosacea phenotype characterized by persistent
    centrofacial erythema, flushing, and telangiectasia without dominant
    papulopustular or phymatous change.
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"
    explanation: >-
      This review explicitly recognizes erythematotelangiectatic rosacea as
      one of the four canonical clinical subtypes.
  - reference: PMID:27718519
    reference_title: "Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The following two features were independently considered diagnostic for rosacea: (i) persistent, centrofacial erythema associated with periodic intensification; and (ii) phymatous changes."
    explanation: >-
      This phenotype-led consensus supports the core vascular features that
      anchor erythematotelangiectatic rosacea.
- name: Papulopustular Rosacea
  description: >-
    Inflammatory rosacea subtype with persistent facial erythema accompanied
    by papules and pustules in the central face.
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"
    explanation: >-
      This review explicitly recognizes papulopustular rosacea as a major
      clinical subtype.
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
    explanation: >-
      This supports the inflammatory papule-pustule phenotype that defines
      papulopustular rosacea.
- name: Phymatous Rosacea
  description: >-
    Tissue-remodeling subtype marked by thickening and hypertrophy of facial
    skin and sebaceous structures, most commonly affecting the nose as
    rhinophyma.
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"
    explanation: >-
      This review explicitly recognizes phymatous rosacea as one of the
      canonical clinical subtypes.
  - reference: PMID:41918801
    reference_title: "CO(2) Laser Resection of Giant Rhinophyma Under Local Anesthesia: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phymatous rosacea (PhR), also known as \"rhinophyma\", refers to a benign condition characterized by the excessive proliferation of sebaceous glands and fibrosis in the facial skin due to rosacea"
    explanation: >-
      This supports the hypertrophic and fibrotic tissue-remodeling pattern
      characteristic of phymatous rosacea.
- name: Ocular Rosacea
  description: >-
    Ocular subtype involving chronic inflammatory disease of the eyelids and
    ocular surface, often with blepharitis, meibomian dysfunction, dryness,
    and photophobia.
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"
    explanation: >-
      This review explicitly recognizes ocular rosacea as a canonical
      rosacea subtype.
  - reference: PMID:40522449
    reference_title: "[Ocular rosacea : Clinical aspects, diagnostics, management and treatment]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular rosacea is a chronic inflammatory disease that affects the surface of the eye and the eyelids."
    explanation: >-
      This supports ocular rosacea as a distinct subtype centered on eyelid
      and ocular surface inflammation.
prevalence:
- population: Worldwide general population (pooled, 41 populations)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 5460.0
  rate_low: 4910.0
  rate_high: 6040.0
  notes: >-
    Proportion meta-analysis of 32 studies (26,519,836 individuals; 22 of 41
    populations European). Pooled 5.46% (95% CI 4.91-6.04); women 5.41%,
    men 3.90%, peak at ages 45-60. Estimates are method-dependent: higher
    in symptom questionnaires, lower in ICD-coded registries.
  evidence:
  - reference: PMID:29478264
    reference_title: "Incidence and prevalence of rosacea: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pooled proportion of individuals with rosacea was 5·46% [95% confidence interval (CI) 4·91-6·04] in the general population and 2·39% (95% CI 1·56-3·39) among dermatological outpatients."
    explanation: >-
      Pooled general-population point prevalence from the meta-analysis.
  - reference: PMID:29478264
    reference_title: "Incidence and prevalence of rosacea: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Self-reported rosacea gave higher prevalence estimates than rosacea diagnosed by clinical examination, suggesting a low specificity of questionnaires based on symptoms."
    explanation: >-
      Documents the ascertainment dependence behind the wide range of
      published estimates.
- population: Dermatological outpatients (pooled)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 2390.0
  rate_low: 1560.0
  rate_high: 3390.0
  notes: >-
    Same meta-analysis; proportion of dermatology outpatient attendances
    with rosacea (2.39%, 95% CI 1.56-3.39), a clinic-based rather than
    population denominator.
  evidence:
  - reference: PMID:29478264
    reference_title: "Incidence and prevalence of rosacea: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pooled proportion of individuals with rosacea was 5·46% [95% confidence interval (CI) 4·91-6·04] in the general population and 2·39% (95% CI 1·56-3·39) among dermatological outpatients."
    explanation: >-
      Pooled outpatient-clinic prevalence from the same meta-analysis.
pathophysiology:
- name: Skin barrier dysfunction
  description: >-
    Epidermal barrier disruption amplifies inflammatory signaling in rosacea
    and serves as an early permissive event for downstream innate immune
    activation.
  biological_processes:
  - preferred_term: establishment of skin barrier
    term:
      id: GO:0061436
      label: establishment of skin barrier
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  downstream:
  - target: Pro-cathelicidin transcription
    description: >-
      Barrier-disrupting triggers increase keratinocyte pro-cathelicidin
      transcription.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28150107
      reference_title: "Acne and Rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The sequence of innate immune activation in rosacea starts with factors increasing keratinocyte transcription of pro-cathelicidin (including vitamin D activated by UV, UV itself, infection, injury, and other triggers to barrier disruption)"
      explanation: >-
        This directly links barrier-disrupting triggers to increased
        pro-cathelicidin transcription in rosacea keratinocytes.
  - target: STAT3-mediated cytokine signaling
    description: >-
      Barrier injury activates a keratinocyte cytokine-signaling program
      centered on STAT3.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35392024
      reference_title: "Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "our results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea partly by activating STAT3-mediated cytokine signal pathways in keratinocytes."
      explanation: >-
        This directly supports barrier dysfunction as an upstream driver
        of STAT3-mediated cytokine signaling.
  evidence:
  - reference: PMID:35392024
    reference_title: "Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea partly by activating STAT3-mediated cytokine signal pathways in keratinocytes."
    explanation: >-
      This study establishes barrier dysfunction as a disease-amplifying
      mechanism in rosacea.
- name: Demodex Folliculorum Proliferation
  description: >-
    Demodex folliculorum mite density in facial pilosebaceous units is
    substantially increased in rosacea skin relative to healthy controls.
    Mites secrete bioactive molecules that modulate Toll-like receptor
    signaling in sebocytes and are increasingly recognized as a trigger of
    the innate immune inflammatory cascade rather than an incidental
    commensal finding.
  locations:
  - preferred_term: pilosebaceous unit
    term:
      id: UBERON:0011932
      label: pilosebaceous unit
  downstream:
  - target: TLR2 upregulation
    description: >-
      Demodex mites secrete bioactive molecules that modulate Toll-like
      receptor signaling and increase TLR2 receptor expression, initially
      characterized in sebocytes, contributing to the broader innate immune
      TLR2 activation seen in rosacea skin. The supporting measurement is in
      sebocytes while the target node is scoped to keratinocytes, so the
      edge carries an extrapolation across cell type; that is an epistemic
      caveat, recorded here and in the evidence item's directness, not a
      step in the causal chain.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - mite-secreted bioactive molecules engaging pattern-recognition signalling
    evidence:
    - reference: PMID:29532463
      reference_title: "Demodex mites modulate sebocyte immune reaction: possible role in the pathogenesis of rosacea."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Demodex secreted bioactive molecules that affected TLR2 receptor expression by sebocytes."
      explanation: >-
        Direct experimental evidence that Demodex mites modulate TLR2
        expression, supporting Demodex proliferation as an upstream driver
        of TLR2 upregulation; the finding is in sebocytes rather than the
        keratinocytes referenced by the target node, so the extrapolation
        to the broader skin TLR2 phenomenon is indirect.
  - target: Sebaceous gland dysfunction
    description: >-
      Live Demodex mites directly stimulate sebocytes in culture, altering
      Toll-like receptor pathway gene and protein expression and inducing
      proinflammatory cytokine secretion, implicating the sebaceous unit as
      a site of mite-host immune interaction.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29532463
      reference_title: "Demodex mites modulate sebocyte immune reaction: possible role in the pathogenesis of rosacea."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: "High numbers of Demodex induced proinflammatory cytokine secretion, whereas lower numbers did not."
      explanation: >-
        Supports a direct, mite-load-dependent inflammatory interaction
        between Demodex and sebaceous-unit sebocytes. Graded DIRECT, unlike
        the sibling TLR2 edge from the same paper, because SZ95 sebocytes
        are the sebaceous gland's own cell type, so no cross-cell-type
        extrapolation is involved.
  evidence:
  - reference: PMID:23171449
    reference_title: "Quantification of Demodex folliculorum by PCR in rosacea and its relationship to skin innate immune activation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "D. folliculorum density was 5.7 times higher in rosacea patients than in healthy volunteers."
    explanation: >-
      Quantitative PCR study establishing markedly increased Demodex
      folliculorum density as a feature of rosacea skin.
  - reference: PMID:33095403
    reference_title: "The Pathogenic Role of Demodex Mites in Rosacea: A Potential Therapeutic Target Already in Erythematotelangiectatic Rosacea?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Demodex mite is beginning to be accepted as one of the triggers of this inflammatory cascade, and its proliferation as a marker of rosacea"
    explanation: >-
      Review supporting Demodex proliferation as a recognized trigger of
      the rosacea inflammatory cascade rather than an incidental finding.
- name: Pro-cathelicidin transcription
  description: >-
    Keratinocytes in rosacea upregulate pro-cathelicidin transcription,
    creating substrate for downstream proteolytic generation of inflammatory
    peptides.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  downstream:
  - target: LL-37 generation
    description: >-
      Increased pro-cathelicidin availability supports downstream formation
      of LL-37 after proteolytic processing.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - kallikrein-mediated cathelicidin cleavage
    evidence:
    - reference: PMID:28150107
      reference_title: "Acne and Rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"
      explanation: >-
        This supports cathelicidin-processing output to LL-37 downstream
        of increased pro-cathelicidin availability.
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The sequence of innate immune activation in rosacea starts with factors increasing keratinocyte transcription of pro-cathelicidin"
    explanation: >-
      This review explicitly places pro-cathelicidin transcription near the
      start of rosacea innate immune activation.
- name: TLR2 upregulation
  description: >-
    Keratinocyte TLR2 expression is increased in rosacea and sensitizes skin
    to environmental and microbial stimuli.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  downstream:
  - target: KLK5/KLK7 activation
    description: >-
      Increased TLR2 signaling promotes activation of kallikrein-family
      serine proteases.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28150107
      reference_title: "Acne and Rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the serine proteases of the KLK family, KLK5 and KLK7 (activation mediated by TLR-2, which is upregulated by environmental and microbial stimuli)"
      explanation: >-
        This directly supports TLR2 as an upstream driver of KLK5/KLK7
        activation in rosacea.
  evidence:
  - reference: PMID:39823143
    reference_title: "Unveiling the Molecular Mechanisms of Rosacea: Insights From Transcriptomics and In Vitro Experiments."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Specifically, Toll-like receptor 2 (TLR2) and S100A9 proteins were upregulated, potentially promoting these processes."
    explanation: >-
      This study supports increased TLR2 expression as part of rosacea
      inflammatory activation.
- name: KLK5/KLK7 activation
  description: >-
    Kallikrein-family serine proteases are activated downstream of TLR2 and
    participate in cathelicidin processing.
  downstream:
  - target: LL-37 generation
    description: >-
      Activated KLK5/KLK7 cleave pro-cathelicidin to generate LL-37 and
      related peptides.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28150107
      reference_title: "Acne and Rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"
      explanation: >-
        This supports KLK-mediated proteolytic generation of LL-37.
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the serine proteases of the KLK family, KLK5 and KLK7 (activation mediated by TLR-2, which is upregulated by environmental and microbial stimuli)"
    explanation: >-
      This review identifies KLK5/KLK7 as activated proteases in rosacea
      innate immune signaling.
- name: LL-37 generation
  description: >-
    Proteolytic cathelicidin processing yields LL-37 and related peptides
    with inflammatory and angiogenic activity.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
  downstream:
  - target: NLRP3 Inflammasome Activation
    hypothesis_groups:
    - ll37_nlrp3_il1b_papulopustular
    description: >-
      LL-37 activates the NLRP3 inflammasome, among other downstream
      pathways, driving pro-inflammatory cytokine production; in mice the
      LL-37-induced inflammatory infiltrate is NLRP3-dependent.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42325915
      reference_title: "Neurohormonal-Immune Dysregulation in Rosacea: Emerging Perspectives from the Skin-Gut-Brain Axis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "LL-37 subsequently activates multiple downstream pathways, including NF-κB, the NLRP3 inflammasome, and JAK/STAT, leading to the production of pro-inflammatory cytokines."
      explanation: >-
        Review synthesis placing NLRP3 inflammasome activation directly
        downstream of LL-37.
    - reference: PMID:33745908
      reference_title: "Antimicrobial Peptide LL-37 Drives Rosacea-Like Skin Inflammation in an NLRP3-Dependent Manner."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "intradermal LL-37 administration induced in vivo caspase-1 activation and ASC speck formation in the skin of Nlrp3-expressing, but not in Nlrp3-deficient, mice."
      explanation: >-
        Genetic loss-of-function evidence for the edge: LL-37-induced
        inflammasome activation in skin requires NLRP3.
    - reference: PMID:33745908
      reference_title: "Antimicrobial Peptide LL-37 Drives Rosacea-Like Skin Inflammation in an NLRP3-Dependent Manner."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: "LL-37 promotes NLRP3-mediated inflammasome activation in lipopolysaccharide-primed macrophages, indicated by the processing of caspase-1 and IL-1β."
      explanation: >-
        Cell-level demonstration that LL-37 is sufficient to activate the
        NLRP3 inflammasome, with caspase-1 and IL-1beta processing as the
        readout.
    - reference: PMID:37185701
      reference_title: "Long-Term Administration of LL-37 Can Induce Irreversible Rosacea-like Lesion."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "A recent study found that the intradermal injection of LL-37 (300 μM) into mice could induce the infiltration of inflammatory cells in an NLRP3-dependent manner, thereby participating in the pathogenesis of rosacea [20]."
      explanation: >-
        Mouse evidence that the LL-37 inflammatory response requires NLRP3;
        reported second-hand in this paper's introduction rather than as
        its own result, hence indirect.
  - target: Mast cell-mediated amplification
    description: >-
      Cathelicidin signaling recruits mast-cell-dependent amplification of
      inflammation and vascular reactivity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28150107
      reference_title: "Acne and Rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mast cells are pivotal mediators of cathelicidin-initiated skin inflammation"
      explanation: >-
        This directly supports mast cells as downstream mediators of
        cathelicidin signaling.
  - target: Angiogenic vascular remodeling
    description: >-
      LL-37 and related peptides promote angiogenic changes in cutaneous
      vasculature.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28150107
      reference_title: "Acne and Rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"
      explanation: >-
        This directly supports an angiogenic vascular effect downstream of
        LL-37 generation.
  - target: Th1/Th17 adaptive inflammation
    description: >-
      LL-37-exposed keratinocytes induce chemokine programs that recruit
      pathogenic T cells and strengthen adaptive inflammatory polarization.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - CXCL10 induction
    - Jak1/STAT1 signaling
    evidence:
    - reference: PMID:40835085
      reference_title: "Cathelicidin LL-37-Induced Transcriptome of Human Keratinocyte Identifies Chemokine CXCL10 Link to T-Cell-Mediated Rosacea Pathogenesis through Jak1/STAT1 Pathway."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Mechanistically, LL-37-induced CXCL10 production relied on the Jak1/signal transducer and activator of transcription 1 signaling pathway."
      explanation: >-
        This supports a mechanistic bridge from LL-37 exposure to
        chemokine-driven adaptive inflammatory recruitment.
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"
    explanation: >-
      This review identifies LL-37 generation as a key inflammatory and
      angiogenic step in rosacea.
  - reference: PMID:40835085
    reference_title: "Cathelicidin LL-37-Induced Transcriptome of Human Keratinocyte Identifies Chemokine CXCL10 Link to T-Cell-Mediated Rosacea Pathogenesis through Jak1/STAT1 Pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Abnormal overexpression of human antimicrobial peptide LL-37 is a hallmark of rosacea."
    explanation: >-
      This study reinforces LL-37 overexpression as a central proximal
      mechanism in rosacea biology.
  - reference: PMID:41087666
    reference_title: "LAPTM5 exacerbates STING-mediated inflammation induced by LL-37 through stabilizing STING in rosacea."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Both STING antagonist H-151 and LAPTM5 knockdown alleviate LL-37-induced rosacea-like phenotypes."
    explanation: >-
      This model-organism evidence supports LL-37 as a proximal inducer of
      rosacea-like inflammatory disease programs.
- name: Mast cell-mediated amplification
  description: >-
    Mast cells amplify cathelicidin-initiated inflammation and increase local
    vasodilation within rosacea lesions.
  cell_types:
  - preferred_term: mast cell
    term:
      id: CL:0000097
      label: mast cell
  downstream:
  - target: Neurovascular vasodilation
    description: >-
      Mast-cell activation promotes vasodilatory responses in affected skin.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28150107
      reference_title: "Acne and Rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mast cells are pivotal mediators of cathelicidin-initiated skin inflammation—amplifying inflammation, vasodilation, and generation of LL-37"
      explanation: >-
        This directly supports mast cells as mediators of vasodilation in
        rosacea lesions.
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mast cells are pivotal mediators of cathelicidin-initiated skin inflammation—amplifying inflammation, vasodilation, and generation of LL-37"
    explanation: >-
      This review places mast cells in an amplification loop that increases
      inflammatory and vascular disease activity.
- name: STAT3-mediated cytokine signaling
  description: >-
    Keratinocyte STAT3-centered cytokine signaling links barrier injury to
    inflammatory persistence and immune-cell recruitment.
  biological_processes:
  - preferred_term: cytokine-mediated signaling pathway
    term:
      id: GO:0019221
      label: cytokine-mediated signaling pathway
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  downstream:
  - target: Immune cell infiltration
    description: >-
      STAT3 activation promotes immune-cell accumulation within rosacea
      lesions.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35392024
      reference_title: "Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "STAT3 could contribute to the progression of rosacea partly by dysregulating immune infiltration via activating the cytokine/chemokines signal."
      explanation: >-
        This directly links STAT3-mediated cytokine signaling to increased
        immune infiltration in rosacea.
  evidence:
  - reference: PMID:35392024
    reference_title: "Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea partly by activating STAT3-mediated cytokine signal pathways in keratinocytes."
    explanation: >-
      This study identifies STAT3-mediated cytokine signaling as a key
      inflammatory amplifier in rosacea.
- name: ACSL5-Mediated Lipid Metabolism Dysregulation
  description: >-
    Transcriptomic profiling of erythematotelangiectatic rosacea (ETR) skin
    identifies differentially expressed genes enriched in lipid metabolism
    pathways, with ACSL5 and ACADVL nominated as hub genes by network
    analysis. This is a single-study, emerging finding rather than an
    established mechanism.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  subtypes:
  - Erythematotelangiectatic Rosacea
  downstream:
  - target: Immune cell infiltration
    hypothesis_groups:
    - etr_lipid_metabolism_acsl5_macrophage
    description: >-
      In a rosacea mouse model, ACSL5 upregulation co-localizes with
      increased M1 macrophage infiltration, suggesting a mechanistic link
      between lipid-metabolic dysregulation and macrophage-driven
      inflammation, though the finding is correlative (co-localization)
      rather than a demonstrated causal perturbation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - lipid metabolic reprogramming
    - M1 macrophage polarization
    evidence:
    - reference: PMID:40195491
      reference_title: "ACSL5 mediates macrophage infiltration and lipid metabolism in erythrotelangiectasia rosacea via potential pathogenic mechanisms and therapeutic targets."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Immunofluorescence validation confirmed significant ACSL5 upregulation and increased M1 macrophage infiltration in the rosacea mouse model. The co-localization of ACSL5 with M1 macrophage markers suggests a mechanistic link between lipid metabolism and inflammatory responses."
      explanation: >-
        Mouse-model immunofluorescence supports spatial co-localization of
        ACSL5 upregulation with M1 macrophage infiltration, an indirect
        (correlative) link to immune cell infiltration rather than a
        direct causal perturbation experiment.
  evidence:
  - reference: PMID:40195491
    reference_title: "ACSL5 mediates macrophage infiltration and lipid metabolism in erythrotelangiectasia rosacea via potential pathogenic mechanisms and therapeutic targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified 304 differentially expressed genes in erythrotelangiectasia rosacea (ETR), primarily enriched in lipid metabolism pathways. Support vector machine (SVM), linear regression analyses and network analysis revealed ACADVL and ACSL5 as potential therapeutic targets."
    explanation: >-
      Transcriptomic profiling of patient ETR skin samples supports lipid
      metabolism dysregulation, centered on ACSL5/ACADVL, as a feature of
      this rosacea subtype.
- name: NLRP3 Inflammasome Activation
  description: >-
    Rosacea skin over-expresses inflammasome components (NLRP3/NALP-3,
    caspase-1) together with IL-1beta, most strongly in papulopustular
    disease. Reviews place the inflammasome downstream of LL-37 as one
    route from cathelicidin signaling to IL-1beta maturation and the
    neutrophilic papulopustular lesion; the paired transcriptomic and
    proteomic explant dataset geo:GSE155141 in this entry independently
    implicates IL-1beta as a central lesional mediator.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: NLRP3 inflammasome complex assembly
    modifier: INCREASED
    term:
      id: GO:0044546
      label: NLRP3 inflammasome complex assembly
  - preferred_term: interleukin-1 beta production
    modifier: INCREASED
    term:
      id: GO:0032611
      label: interleukin-1 beta production
  downstream:
  - target: Papulopustular inflammation
    hypothesis_groups:
    - ll37_nlrp3_il1b_papulopustular
    description: >-
      Inflammasome-processed IL-1beta contributes to the neutrophilic
      inflammatory lesion; inflammasome gene expression is highest in the
      papulopustular subtype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - IL-1beta maturation and release
    - neutrophil recruitment
    evidence:
    - reference: PMID:23171449
      reference_title: "Quantification of Demodex folliculorum by PCR in rosacea and its relationship to skin innate immune activation."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Skin sample analysis showed a higher expression of genes encoding pro-inflammatory cytokines (Il-8, Il-1b, TNF-a) and inflammasome-related genes (NALP-3 and CASP-1) in rosacea, especially PPR."
      explanation: >-
        Inflammasome and IL-1beta gene expression is enriched in the
        papulopustular subtype; an expression association, so the edge to
        lesion formation is inferred rather than demonstrated.
  evidence:
  - reference: PMID:23171449
    reference_title: "Quantification of Demodex folliculorum by PCR in rosacea and its relationship to skin innate immune activation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin sample analysis showed a higher expression of genes encoding pro-inflammatory cytokines (Il-8, Il-1b, TNF-a) and inflammasome-related genes (NALP-3 and CASP-1) in rosacea, especially PPR."
    explanation: >-
      Direct measurement of NALP-3 (NLRP3) and CASP-1 over-expression in
      rosacea facial skin samples.
  - reference: PMID:33745908
    reference_title: "Antimicrobial Peptide LL-37 Drives Rosacea-Like Skin Inflammation in an NLRP3-Dependent Manner."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "LL-37-induced rosacea-like skin inflammation was significantly abrogated in Nlrp3-deficient mice."
    explanation: >-
      Establishes NLRP3 as required for the rosacea-like inflammatory
      phenotype in the LL-37 model, and the same study shows the NLRP3
      inhibitor MCC950 reduces it.
  notes: >-
    A dataset-analysis run on the paired papulopustular explant series
    geo:GSE155141 (kb/hypotheses/Rosacea/ll37_nlrp3_il1b_papulopustular/)
    found IL-1beta induces NLRP3 mRNA in non-lesional explants (paired
    p = 0.025, not FDR-significant at n = 5) but no steady-state lesional
    versus non-lesional change in NLRP3, CASP1, PYCARD, IL1B or IL18. That
    null does not reproduce the PPR-enriched over-expression reported by
    Casas 2012 at the transcript level; the node's support therefore rests
    mainly on the mouse loss-of-function evidence and the LL-37 axis, not
    on lesional expression.
- name: Pro-inflammatory Fibroblast Expansion
  description: >-
    Single-cell transcriptomics of lesional facial skin (131,243 cells from
    nine women with rosacea and three controls) identifies fibroblasts as
    the leading source of pro-inflammatory and vasodilatory signals, with
    expansion of a pro-inflammatory fibroblast population in papulopustular
    disease. Fibroblast depletion, or knockdown of the fibroblast-specific
    gene PTGDS, blocks rosacea-like disease in mice. This reframes the
    keratinocyte-centred TLR2-KLK5-LL-37 model as a multicellular circuit
    in which dermal fibroblasts amplify both inflammation and vasodilation.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: pro-inflammatory dermal fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  subtypes:
  - Papulopustular Rosacea
  downstream:
  - target: Neurovascular vasodilation
    hypothesis_groups:
    - phyma_fibroblast_identity
    description: >-
      Fibroblasts are the leading cell type producing vasodilative signals
      in rosacea skin.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39384741
      reference_title: "Single-cell transcriptomics reveals aberrant skin-resident cell populations and identifies fibroblasts as a determinant in rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most importantly, fibroblasts are identified as the leading cell type producing pro-inflammatory and vasodilative signals in rosacea."
      explanation: >-
        Single-cell ligand analysis places fibroblasts upstream of the
        vasodilatory signaling in lesional skin.
  - target: Immune cell infiltration
    hypothesis_groups:
    - phyma_fibroblast_identity
    description: >-
      Fibroblast-derived pro-inflammatory signals sustain lesional
      inflammation; removing fibroblasts or PTGDS blocks rosacea-like
      disease in mice.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - fibroblast-derived cytokine and chemokine signaling
    evidence:
    - reference: PMID:39384741
      reference_title: "Single-cell transcriptomics reveals aberrant skin-resident cell populations and identifies fibroblasts as a determinant in rosacea."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Depletion of fibroblasts or knockdown of PTGDS, a gene specifically upregulated in fibroblasts, blocks rosacea development in mice."
      explanation: >-
        Loss-of-function in mice shows fibroblasts are required for the
        inflammatory phenotype; the specific edge to immune infiltration is
        inferred from that requirement.
  evidence:
  - reference: PMID:39384741
    reference_title: "Single-cell transcriptomics reveals aberrant skin-resident cell populations and identifies fibroblasts as a determinant in rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The papulopustular rosacea is featured by expansion of pro-inflammatory fibroblasts, Schwann, endothelial and macrophage/dendritic cells."
    explanation: >-
      Single-cell census documenting the pro-inflammatory fibroblast
      expansion in papulopustular lesions.
  - reference: PMID:39384741
    reference_title: "Single-cell transcriptomics reveals aberrant skin-resident cell populations and identifies fibroblasts as a determinant in rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most importantly, fibroblasts are identified as the leading cell type producing pro-inflammatory and vasodilative signals in rosacea."
    explanation: >-
      Identifies fibroblasts as the dominant signal-producing population.
- name: Immune cell infiltration
  description: >-
    Rosacea lesions show increased immune-cell infiltration that reinforces
    inflammatory lesion formation.
  downstream:
  - target: Papulopustular inflammation
    description: >-
      Increased lesional immune infiltration supports development of
      inflammatory papules and pustules.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35392024
      reference_title: "Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "our results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea"
      explanation: >-
        This supports immune infiltration as part of the inflammatory
        lesion-forming program in rosacea.
  evidence:
  - reference: PMID:35392024
    reference_title: "Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The XCell immune cell assays showed that the increased immune infiltration with SBD."
    explanation: >-
      This transcriptomic analysis supports increased immune-cell
      infiltration in rosacea with barrier dysfunction.
- name: Th1/Th17 adaptive inflammation
  description: >-
    Chemokine and cytokine networks in rosacea polarize adaptive immunity
    toward Th1/Th17 inflammatory programs.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  downstream:
  - target: Papulopustular inflammation
    description: >-
      Th1/Th17-skewed adaptive inflammation contributes to inflammatory
      papulopustular lesions.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28150107
      reference_title: "Acne and Rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Chemokine and cytokine signals interact to generate a Th1/Th17-polarized adaptive immune response in rosacea"
      explanation: >-
        This supports an adaptive inflammatory branch converging on
        papulopustular disease activity.
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chemokine and cytokine signals interact to generate a Th1/Th17-polarized adaptive immune response in rosacea"
    explanation: >-
      This review supports a Th1/Th17-polarized adaptive inflammatory
      response in rosacea.
  - reference: PMID:40835085
    reference_title: "Cathelicidin LL-37-Induced Transcriptome of Human Keratinocyte Identifies Chemokine CXCL10 Link to T-Cell-Mediated Rosacea Pathogenesis through Jak1/STAT1 Pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "T-cell recruiting chemokine CXCL10 turns out to be the most abundant inflammatory mediator overexpressed upon LL-37 exposure."
    explanation: >-
      This supports a chemokine-driven adaptive immune arm linking
      keratinocyte activation to pathogenic T-cell recruitment.
- name: TRP and neuropeptide signaling
  description: >-
    TRP-channel activation and neuropeptide signaling form a neurocutaneous
    branch of rosacea pathophysiology that increases vascular reactivity.
  biological_processes:
  - preferred_term: neuropeptide signaling pathway
    term:
      id: GO:0007218
      label: neuropeptide signaling pathway
  downstream:
  - target: Neurovascular vasodilation
    description: >-
      TRP and neuropeptide signaling promote exaggerated vasodilatory
      responses in rosacea skin.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34035646
      reference_title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Recognized mechanisms include the innate immune system, with the implication of Toll-like receptors (TLRs) and cathelicidins; neurovascular deregulation involving vascular endothelial growth factor (VEGF), transient receptor potential (TRP) ion channels, and neuropeptides"
      explanation: >-
        This directly supports TRP and neuropeptides as upstream drivers
        of rosacea neurovascular dysregulation.
  evidence:
  - reference: PMID:34035646
    reference_title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recognized mechanisms include the innate immune system, with the implication of Toll-like receptors (TLRs) and cathelicidins; neurovascular deregulation involving vascular endothelial growth factor (VEGF), transient receptor potential (TRP) ion channels, and neuropeptides"
    explanation: >-
      This review identifies TRP and neuropeptides as part of the
      neurovascular arm of rosacea pathophysiology.
- name: Neurovascular vasodilation
  description: >-
    Exaggerated vasodilation is a proximal vascular event that drives flushing
    and contributes to persistent background erythema.
  biological_scale: TISSUE
  downstream:
  - target: Flushing
    description: Vasodilatory surges produce episodic flushing.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28150107
      reference_title: "Acne and Rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema)"
      explanation: >-
        This supports flushing as a direct clinical output of vascular
        hyperreactivity in rosacea.
  - target: Persistent centrofacial erythema
    description: >-
      Recurrent vasodilatory instability contributes to chronic background
      centrofacial erythema.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - recurrent vascular hyperreactivity
    - persistent superficial vasodilation
    evidence:
    - reference: PMID:27718519
      reference_title: "Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "persistent, centrofacial erythema associated with periodic intensification"
      explanation: >-
        This supports persistent erythema as a chronic vascular phenotype
        that periodically intensifies.
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "while the multifactorial pathology of rosacea is thought to involve both vasoactive and neurocutaneous mechanisms."
    explanation: >-
      This overview supports a vasoreactive proximal mechanism in rosacea.
- name: Angiogenic vascular remodeling
  description: >-
    Angiogenic signaling contributes to persistent vascular remodeling and
    visible superficial telangiectatic change.
  biological_processes:
  - preferred_term: angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
  downstream:
  - target: Facial telangiectasia
    description: >-
      Persistent angiogenic remodeling contributes to telangiectatic
      centrofacial vessels.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37626650
      reference_title: "Exploring the Pathogenesis and Mechanism-Targeted Treatments of Rosacea: Previous Understanding and Updates."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Rosacea is a chronic inflammatory skin disease characterized by recurrent erythema, flushing, telangiectasia, papules, pustules, and phymatous changes in the central area of the face."
      explanation: >-
        This supports telangiectasia as a major downstream vascular
        manifestation of rosacea.
  - target: Persistent centrofacial erythema
    description: >-
      Remodeling of superficial vasculature helps sustain background facial
      erythema.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - superficial vascular enlargement
    - persistent cutaneous hyperemia
    evidence:
    - reference: PMID:28150107
      reference_title: "Acne and Rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"
      explanation: >-
        This supports an angiogenic component in the pathway that sustains
        persistent erythematous change.
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"
    explanation: >-
      This supports angiogenic signaling as a discrete downstream consequence
      of cathelicidin pathway activation.
  - reference: PMID:40567003
    reference_title: "Novel Molecular Subtyping Revealed Molecular Pathways That Contribute to the Pathogenesis of Rosacea."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "angiogenesis and neutrophil activation may contribute to persistent erythema and a large number of papules and pustules in the severe stage of rosacea."
    explanation: >-
      This molecular subtyping study supports angiogenesis as a driver of
      persistent erythema and lesion-rich severe rosacea.
- name: Papulopustular inflammation
  description: >-
    Convergent innate, adaptive, and keratinocyte inflammatory programs
    produce inflammatory papules and pustules in papulopustular rosacea.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  downstream:
  - target: Papules
    description: Inflammatory lesion formation produces papular eruptions.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28150107
      reference_title: "Acne and Rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
      explanation: >-
        This directly supports papules as a downstream inflammatory lesion
        type in rosacea.
  - target: Pustules
    description: Ongoing inflammatory lesion formation produces pustules.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28150107
      reference_title: "Acne and Rosacea."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
      explanation: >-
        This directly supports pustules as a downstream inflammatory lesion
        type in rosacea.
  evidence:
  - reference: PMID:39823143
    reference_title: "Unveiling the Molecular Mechanisms of Rosacea: Insights From Transcriptomics and In Vitro Experiments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transcriptomic analysis revealed significantly elevated expression of inflammatory-related genes in rosacea patients."
    explanation: >-
      This study supports a lesion-forming inflammatory state in rosacea
      skin.
- name: Sebaceous gland dysfunction
  description: >-
    Dysfunction of cutaneous sebaceous glands is recognized as part of the
    multifactorial tissue biology of rosacea.
  downstream:
  - target: Sebaceous gland and soft tissue hyperplasia/fibrosis
    description: >-
      In advanced disease, altered sebaceous-unit biology can progress to
      hyperplastic and fibrotic phymatous tissue remodeling.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - chronic inflammation
    - connective tissue remodeling
    evidence:
    - reference: PMID:19428039
      reference_title: "[Rhinophyma in a black African male patient]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Rhinophyma is an irregular and progressive nasal hypertrophy, due to hyperplasia and fibrosis of the sebaceous glands and surrounding soft tissues."
      explanation: >-
        This supports progression from abnormal sebaceous-unit biology to
        sebaceous and soft-tissue hyperplasia/fibrosis in phymatous
        rosacea.
  evidence:
  - reference: PMID:34035646
    reference_title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recognized mechanisms include the innate immune system, with the implication of Toll-like receptors (TLRs) and cathelicidins; neurovascular deregulation involving vascular endothelial growth factor (VEGF), transient receptor potential (TRP) ion channels, and neuropeptides; and dysfunction of skin sebaceous glands and ocular meibomian glands."
    explanation: >-
      This review identifies sebaceous gland dysfunction as a discrete
      component of rosacea pathophysiology.
- name: Meibomian gland dysfunction
  description: >-
    Ocular rosacea includes meibomian gland dysfunction as part of its
    site-specific pathophysiology.
  downstream:
  - target: Ocular surface and eyelid inflammation
    description: >-
      Meibomian-gland disease contributes to chronic inflammatory
      involvement of the eyelids and ocular surface.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40522449
      reference_title: "[Ocular rosacea : Clinical aspects, diagnostics, management and treatment]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It is characterized by bilateral chronic posterior blepharitis and meibomitis, which can involve the entire surface of the eye, including the cornea, during the course of the disease."
      explanation: >-
        This directly links meibomian disease to chronic inflammatory
        involvement of the eyelids and ocular surface in ocular rosacea.
  evidence:
  - reference: PMID:34035646
    reference_title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recognized mechanisms include the innate immune system, with the implication of Toll-like receptors (TLRs) and cathelicidins; neurovascular deregulation involving vascular endothelial growth factor (VEGF), transient receptor potential (TRP) ion channels, and neuropeptides; and dysfunction of skin sebaceous glands and ocular meibomian glands."
    explanation: >-
      This review identifies meibomian gland dysfunction as part of ocular
      rosacea biology.
- name: Ocular surface and eyelid inflammation
  description: >-
    Ocular rosacea produces chronic inflammatory involvement of the eyelids
    and ocular surface, with posterior blepharitis as a characteristic
    clinical expression.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  downstream:
  - target: Blepharitis
    description: >-
      Chronic eyelid inflammation manifests clinically as posterior
      blepharitis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40522449
      reference_title: "[Ocular rosacea : Clinical aspects, diagnostics, management and treatment]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It is characterized by bilateral chronic posterior blepharitis and meibomitis, which can involve the entire surface of the eye, including the cornea, during the course of the disease."
      explanation: >-
        This directly supports blepharitis as a downstream phenotype of
        ocular rosacea inflammatory eyelid disease.
  evidence:
  - reference: PMID:40522449
    reference_title: "[Ocular rosacea : Clinical aspects, diagnostics, management and treatment]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular rosacea is a chronic inflammatory disease that affects the surface of the eye and the eyelids."
    explanation: >-
      This review supports ocular rosacea as an inflammatory disease of the
      eyelids and ocular surface.
- name: Fibrotic dermal remodeling
  description: >-
    Advanced rosacea can shift toward a fibrotic remodeling program in which
    vascular changes are coupled to connective-tissue fibrosis.
  downstream:
  - target: Sebaceous gland and soft tissue hyperplasia/fibrosis
    description: >-
      Fibrotic remodeling progresses to phymatous tissue overgrowth
      involving sebaceous units and surrounding soft tissue.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25151931
      reference_title: "[Physiopathology of rosacea]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Finaly, rhinophyma is linked to both vascular changes and activation of fibrosis, involving TGF beta."
      explanation: >-
        This supports a fibrotic remodeling step in advanced phymatous
        rosacea.
  evidence:
  - reference: PMID:25151931
    reference_title: "[Physiopathology of rosacea]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Finaly, rhinophyma is linked to both vascular changes and activation of fibrosis, involving TGF beta."
    explanation: >-
      This review supports fibrosis as a specific mechanism underlying
      rhinophyma development.
  - reference: PMID:41139274
    reference_title: "Integrated Multi-Omics and Experimental Validation Unveil the GZMK/NF-κB Axis Driving Inflammation and Fibroblast Proliferation in Rosacea: A Novel Drug Target Selection Strategy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "GZMK also promoted cell proliferation and inflammatory factors (including IL-1β, IL-6, and TNFα) production in fibroblasts through activating the NF-κB pathway in vitro."
    explanation: >-
      This directly supports fibroblast proliferative and inflammatory
      programs that can feed fibrotic remodeling in advanced rosacea.
- name: Sebaceous gland and soft tissue hyperplasia/fibrosis
  description: >-
    Rhinophyma reflects progressive hypertrophic remodeling of sebaceous
    glands and adjacent soft tissue in the nose.
  downstream:
  - target: Phymatous change of the nose
    description: >-
      Hyperplastic and fibrotic tissue overgrowth produces the bulbous,
      progressively deformed nasal phenotype of rhinophyma.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19428039
      reference_title: "[Rhinophyma in a black African male patient]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Rhinophyma is an irregular and progressive nasal hypertrophy, due to hyperplasia and fibrosis of the sebaceous glands and surrounding soft tissues."
      explanation: >-
        This directly supports phymatous nasal change as the clinical
        result of sebaceous-gland and soft-tissue hyperplasia/fibrosis.
  evidence:
  - reference: PMID:19428039
    reference_title: "[Rhinophyma in a black African male patient]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rhinophyma is an irregular and progressive nasal hypertrophy, due to hyperplasia and fibrosis of the sebaceous glands and surrounding soft tissues."
    explanation: >-
      This abstract defines rhinophyma in terms of sebaceous-gland and soft
      tissue hyperplasia/fibrosis.
mechanistic_hypotheses:
- hypothesis_group_id: etr_lipid_metabolism_acsl5_macrophage
  hypothesis_label: >-
    Lipid-metabolic reprogramming centred on ACSL5 accompanies, and may
    promote, macrophage infiltration in erythematotelangiectatic rosacea
  status: EMERGING
  applies_to_subtypes:
  - Erythematotelangiectatic Rosacea
  description: >-
    Transcriptomic profiling of ETR skin (GEO GSE65914, 14 ETR versus 20
    control biopsies) enriches for lipid-metabolism and PPAR-signaling
    genes, with ACSL5 and ACADVL nominated as hub genes, and ACSL5
    co-localizes with M1 macrophage markers in a rosacea mouse model. The
    hypothesis is that fatty-acid metabolic reprogramming in lesional skin
    is upstream of macrophage-driven inflammation in the vascular subtype,
    rather than a bystander of it. It rests on a single WGCNA study plus
    co-localization, so the ACSL5 pathophysiology node carries
    mechanism_confidence PROVISIONAL. A confirmatory re-analysis of
    GSE65914 asks whether the lipid-metabolism signature and the ACSL5/ACADVL
    hub genes reproduce in ETR under a prespecified contrast, and whether
    they track macrophage marker expression (CD68, CD163, CD86) within the
    same samples. Downstream causal edges that belong to this hypothesis opt
    in via hypothesis_groups: [etr_lipid_metabolism_acsl5_macrophage].
  evidence:
  - reference: PMID:40195491
    reference_title: "ACSL5 mediates macrophage infiltration and lipid metabolism in erythrotelangiectasia rosacea via potential pathogenic mechanisms and therapeutic targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified 304 differentially expressed genes in erythrotelangiectasia rosacea (ETR), primarily enriched in lipid metabolism pathways. Support vector machine (SVM), linear regression analyses and network analysis revealed ACADVL and ACSL5 as potential therapeutic targets."
    explanation: >-
      The originating transcriptomic observation.
  - reference: PMID:40195491
    reference_title: "ACSL5 mediates macrophage infiltration and lipid metabolism in erythrotelangiectasia rosacea via potential pathogenic mechanisms and therapeutic targets."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Immunofluorescence validation confirmed significant ACSL5 upregulation and increased M1 macrophage infiltration in the rosacea mouse model. The co-localization of ACSL5 with M1 macrophage markers suggests a mechanistic link between lipid metabolism and inflammatory responses."
    explanation: >-
      The co-localization on which the causal reading rests; correlative,
      hence the hypothesis rather than an established mechanism.
  notes: >-
    Confirmatory dataset run on geo:GSE65914
    (kb/hypotheses/Rosacea/etr_lipid_metabolism_acsl5_macrophage/,
    assessed PARTIALLY_SUPPORTED): ACSL5 (5.6x), PPARG (4.5x) and ACADVL
    (2.0x) are strongly higher in ETR with CPT1A unchanged, and CD68,
    CD163 and CD86 are all higher (1.4-1.8x), robust to collapsing the
    two replicate arrays per subject. Within ETR, ACSL5 does not correlate
    with any macrophage marker (all q > 0.45), and the CD86/CD163 balance
    shifts toward the M2 marker CD163 with the M2 regulator PPARG up. The
    label was accordingly reworded from "drives M1 macrophage
    infiltration" to the co-occurrence the data support; a driver role and
    M1 polarization remain untested. The original study derived its
    signature from the same series, so this reproduces the analysis, not
    the cohort; independent replication would need a second ETR
    transcriptome, which does not yet exist in a public repository.
- hypothesis_group_id: ll37_nlrp3_il1b_papulopustular
  hypothesis_label: >-
    LL-37 drives papulopustular lesions through NLRP3 inflammasome
    activation and IL-1beta maturation
  status: EMERGING
  applies_to_subtypes:
  - Papulopustular Rosacea
  description: >-
    The cathelicidin fragment LL-37 is a recognized activator of the NLRP3
    inflammasome, rosacea skin over-expresses NALP-3 (NLRP3) and CASP1
    together with IL1B most strongly in papulopustular disease, and the
    LL-37-induced inflammatory infiltrate in mice is reported to be
    NLRP3-dependent. The hypothesis places inflammasome-processed IL-1beta
    as the route from cathelicidin signaling to the neutrophilic papule and
    pustule, distinct from the mast-cell and Th1/Th17 arms of the same
    LL-37 signal. In this entry it is supported by expression associations
    and a review synthesis, not by a human perturbation. A confirmatory
    re-analysis of the paired lesional versus non-lesional papulopustular
    explant RNA-seq (GEO GSE155141), which independently implicated
    IL-1beta, asks whether NLRP3, CASP1, PYCARD, IL1B and IL18 are
    coordinately elevated in lesional skin and further induced by IL-1beta
    treatment of non-lesional explants. Downstream causal edges that belong
    to this hypothesis opt in via hypothesis_groups:
    [ll37_nlrp3_il1b_papulopustular].
  evidence:
  - reference: PMID:23171449
    reference_title: "Quantification of Demodex folliculorum by PCR in rosacea and its relationship to skin innate immune activation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin sample analysis showed a higher expression of genes encoding pro-inflammatory cytokines (Il-8, Il-1b, TNF-a) and inflammasome-related genes (NALP-3 and CASP-1) in rosacea, especially PPR."
    explanation: >-
      Human lesional expression of the inflammasome components, enriched
      in the papulopustular subtype.
  - reference: PMID:42325915
    reference_title: "Neurohormonal-Immune Dysregulation in Rosacea: Emerging Perspectives from the Skin-Gut-Brain Axis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LL-37 subsequently activates multiple downstream pathways, including NF-κB, the NLRP3 inflammasome, and JAK/STAT, leading to the production of pro-inflammatory cytokines."
    explanation: >-
      Review synthesis placing NLRP3 downstream of LL-37.
  notes: >-
    Confirmatory dataset run on geo:GSE155141 (15 samples: paired
    non-lesional and lesional PPR explants, plus IL-1beta-treated
    non-lesional explants;
    kb/hypotheses/Rosacea/ll37_nlrp3_il1b_papulopustular/, assessed
    PARTIALLY_SUPPORTED): IL-1beta raised NLRP3 mRNA (paired p = 0.025,
    dz = 1.57, BH q = 0.196) with IL1B and IL1RN trending up, consistent
    with transcriptional priming of the sensor; the lesional versus
    non-lesional contrast was null for all eight genes and CAMP/KLK5 were
    flat, so the post-translational assembly and maturation steps that
    define the hypothesis remain untested at the transcript level. The
    mouse loss-of-function evidence (PMID:33745908) was promoted onto the
    LL-37 to NLRP3 edge as a result of the run's post-lock literature
    check.
- hypothesis_group_id: gwas_loci_lesional_expression
  hypothesis_label: >-
    Rosacea GWAS susceptibility loci act through altered expression in
    lesional skin, including a TLR1-TLR2 heterodimer axis
  status: EMERGING
  description: >-
    The genome-wide significant rosacea loci fall into two groups: immune
    (HLA-DRA/BTNL2, the HLA class II alleles, IL13, IRF1, TLR1) and
    pigmentation (IRF4, HERC2-OCA2, SLC45A2). The hypothesis is that the
    immune loci are expressed and differentially regulated in lesional
    skin, so that germline susceptibility acts through the innate and
    adaptive inflammatory program modelled in this entry rather than only
    through skin phototype. Aponte et al. found three loci (PSMB9-HLA-DMB,
    HERC2-OCA2, NRXN3-DIO2) differentially expressed in lesional versus
    non-lesional skin, and Chang et al. localized HLA-DRA and BTNL2 protein
    to the perifollicular infiltrate, but the newer Million Veteran Program
    loci, TLR1 in particular, have never been tested this way. TLR1 is the
    obligate heterodimer partner of TLR2 for triacylated lipopeptide
    sensing, so a TLR1 risk allele would be the first germline entry point
    into the TLR2-KLK5-LL-37 axis. An exploratory analysis of the
    subtype-spanning biopsy series (GEO GSE65914) asks whether each locus
    gene is differentially expressed in lesional skin by subtype, and
    whether TLR1 and TLR2 are co-expressed there. This hypothesis has no
    causal edges of its own; it concerns the genetic entries. Downstream
    causal edges that belong to it would opt in via hypothesis_groups:
    [gwas_loci_lesional_expression].
  evidence:
  - reference: PMID:29771307
    reference_title: "Assessment of rosacea symptom severity by genome-wide association study and expression analysis highlights immuno-inflammatory and skin pigmentation genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genes within three loci (PSMB9-HLA-DMA, HERC-OCA2 and NRX3-DIO2) were differentially expressed in a previously published clinical rosacea transcriptomics study that compared lesional to non-lesional samples."
    explanation: >-
      The precedent: GWAS loci already shown to change expression in
      lesional skin, motivating the same test for the remaining loci.
  - reference: PMID:25695682
    reference_title: "Assessment of the genetic basis of rosacea by genome-wide association study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exploratory immunohistochemical analysis of HLA-DRA and BTNL2 expression in papulopustular rosacea lesions from six individuals, including one with the rs763035 variant, revealed staining in the perifollicular inflammatory infiltrate of rosacea for both proteins."
    explanation: >-
      Protein-level lesional expression for the lead HLA-region locus.
  notes: >-
    Exploratory dataset run: geo:GSE65914 with target genes HLA-DRA,
    BTNL2, HLA-DRB1, HLA-DQB1, HLA-DQA1, IL13, IRF1, TLR1, TLR2, IRF4,
    HERC2, OCA2, SLC45A2. The MVP loci come from the GWAS Catalog
    (GCST90476178), which this repository cannot yet cite directly (see
    the dbgap:phs001672 dataset record).
- hypothesis_group_id: phyma_fibroblast_identity
  hypothesis_label: >-
    Rhinophyma fibroblasts are an inflammation-associated activated state
    lacking the POSTN/CTHRC1 scar-persistence program, not a scar-type
    myofibroblast
  status: EMERGING
  applies_to_subtypes:
  - Phymatous Rosacea
  description: >-
    Single-cell transcriptomics of papulopustular rosacea identifies an
    expanded pro-inflammatory fibroblast population, marked by PTGDS, as
    the leading source of inflammatory and vasodilatory signals, and
    fibroblast depletion or PTGDS knockdown blocks disease in mice.
    Rhinophyma, the end-stage phymatous lesion, is clinically fibrotic yet
    reverts toward normal after surgical debulking, unlike hypertrophic
    scar. The hypothesis is that the phyma fibroblast is the same
    inflammation-driven state as the papulopustular fibroblast, persisting
    rather than transitioning to a scar-type myofibroblast, which would
    explain both the reversibility and why the fibrotic remodeling node
    feeds phymatous change. An exploratory comparison of the rhinophyma
    versus hypertrophic scar versus healthy skin single-cell atlas
    (ArrayExpress E-MTAB-16629) against the published papulopustular
    fibroblast markers asks whether rhinophyma fibroblasts carry the PTGDS
    pro-inflammatory signature or the ACTA2/COL1A1 myofibroblast signature
    of scar. Downstream causal edges that belong to this hypothesis opt in
    via hypothesis_groups: [phyma_fibroblast_identity].
  evidence:
  - reference: PMID:39384741
    reference_title: "Single-cell transcriptomics reveals aberrant skin-resident cell populations and identifies fibroblasts as a determinant in rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The papulopustular rosacea is featured by expansion of pro-inflammatory fibroblasts, Schwann, endothelial and macrophage/dendritic cells."
    explanation: >-
      The papulopustular fibroblast population the phyma fibroblast is to
      be compared against.
  - reference: PMID:39384741
    reference_title: "Single-cell transcriptomics reveals aberrant skin-resident cell populations and identifies fibroblasts as a determinant in rosacea."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Depletion of fibroblasts or knockdown of PTGDS, a gene specifically upregulated in fibroblasts, blocks rosacea development in mice."
    explanation: >-
      Establishes PTGDS as the marker and the fibroblast as causal in the
      inflammatory subtype.
  notes: >-
    Exploratory dataset run on arrayexpress:E-MTAB-16629
    (kb/hypotheses/Rosacea/phyma_fibroblast_identity/, assessed
    PARTIALLY_SUPPORTED): in the one rhinophyma donor, PTGDS is lowest in
    rhinophyma fibroblasts (5.0% positive) and highest in healthy
    fibroblasts (54.5%), tracks the quiescent markers CFD and APOD, and
    the PTGDS-high rhinophyma cells are endothelial, so the PTGDS marker
    from papulopustular disease does not transfer and was removed from
    the label. Rhinophyma fibroblasts are ACTA2-activated but POSTN- and
    CTHRC1-low (3.1% and 8.0% positive versus 46.4% and 43.4% in
    hypertrophic scar) with CCL19, CXCL12 and CCL2 above scar levels,
    supporting the non-scar-myofibroblast identity that the label now
    states. One donor per condition, marker-score lineage assignment and
    a proxy signature bound every claim. The papulopustular single-cell
    data of Chen et al. have no public accession, so a joint embedding,
    the analysis that would settle this, was not possible.
phenotypes:
- name: Persistent centrofacial erythema
  category: Dermatological
  frequency: VERY_FREQUENT
  diagnostic: true
  subtype: Erythematotelangiectatic Rosacea
  notes: >-
    Persistent background erythema of the central face is a core diagnostic
    phenotype in modern phenotype-led rosacea classification.
  phenotype_term:
    preferred_term: persistent centrofacial erythema
    term:
      id: HP:0001041
      label: Facial erythema
  evidence:
  - reference: PMID:27718519
    reference_title: "Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The following two features were independently considered diagnostic for rosacea: (i) persistent, centrofacial erythema associated with periodic intensification; and (ii) phymatous changes."
    explanation: >-
      ROSCO identifies persistent centrofacial erythema as one of the two
      diagnostic phenotypes for rosacea.
- name: Flushing
  category: Dermatological
  frequency: FREQUENT
  subtype: Erythematotelangiectatic Rosacea
  notes: Episodic flushing commonly accompanies the vascular phenotype.
  phenotype_term:
    preferred_term: flushing
    term:
      id: HP:0031284
      label: Flushing
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
    explanation: >-
      This overview identifies flushing as a characteristic clinical
      manifestation of rosacea.
- name: Facial telangiectasia
  category: Dermatological
  frequency: FREQUENT
  subtype: Erythematotelangiectatic Rosacea
  phenotype_term:
    preferred_term: facial telangiectasia
    term:
      id: HP:0007380
      label: Facial telangiectasia
  evidence:
  - reference: PMID:37626650
    reference_title: "Exploring the Pathogenesis and Mechanism-Targeted Treatments of Rosacea: Previous Understanding and Updates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rosacea is a chronic inflammatory skin disease characterized by recurrent erythema, flushing, telangiectasia, papules, pustules, and phymatous changes in the central area of the face."
    explanation: >-
      This review includes telangiectasia among the central defining
      manifestations of rosacea.
- name: Papules
  category: Dermatological
  frequency: FREQUENT
  subtype: Papulopustular Rosacea
  phenotype_term:
    preferred_term: erythematous papule
    term:
      id: HP:0030350
      label: Erythematous papule
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
    explanation: >-
      This overview identifies inflammatory papules as a characteristic
      lesion type in rosacea.
- name: Pustules
  category: Dermatological
  frequency: FREQUENT
  subtype: Papulopustular Rosacea
  phenotype_term:
    preferred_term: pustule
    term:
      id: HP:0200039
      label: Pustule
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
    explanation: >-
      This overview identifies papulopustular lesions as part of the core
      clinical spectrum of rosacea.
- name: Phymatous change of the nose
  category: Dermatological
  frequency: OCCASIONAL
  diagnostic: true
  subtype: Phymatous Rosacea
  notes: >-
    Phymatous rosacea is most often expressed as progressive tissue
    thickening of the nose (rhinophyma).
  phenotype_term:
    preferred_term: rhinophyma
    term:
      id: HP:0000414
      label: Bulbous nose
  evidence:
  - reference: PMID:27718519
    reference_title: "Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The following two features were independently considered diagnostic for rosacea: (i) persistent, centrofacial erythema associated with periodic intensification; and (ii) phymatous changes."
    explanation: >-
      ROSCO identifies phymatous change as the second independently
      diagnostic phenotype of rosacea.
- name: Blepharitis
  category: Ophthalmological
  frequency: OCCASIONAL
  subtype: Ocular Rosacea
  notes: Ocular rosacea often presents with eyelid margin inflammation.
  phenotype_term:
    preferred_term: blepharitis
    term:
      id: HP:0000498
      label: Blepharitis
  evidence:
  - reference: PMID:40522449
    reference_title: "[Ocular rosacea : Clinical aspects, diagnostics, management and treatment]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by bilateral chronic posterior blepharitis and meibomitis, which can involve the entire surface of the eye, including the cornea, during the course of the disease."
    explanation: >-
      This directly supports chronic posterior blepharitis as a hallmark
      ocular phenotype of ocular rosacea.
- name: Facial edema
  category: Dermatological
  frequency: VERY_RARE
  notes: >-
    A rare rosacea-associated lymphedematous presentation, often termed
    Morbihan disease, causes chronic persistent facial swelling.
  phenotype_term:
    preferred_term: facial edema
    term:
      id: HP:0000282
      label: Facial edema
  evidence:
  - reference: PMID:41426892
    reference_title: "Multimodal Management of Morbihan Disease: Isotretinoin, Intralesional Triamcinolone, and Ketotifen in a Recalcitrant Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morbihan disease, also known as rosacea-associated solid facial edema, is a rare and chronic condition that presents with persistent facial swelling and often proves difficult to treat."
    explanation: >-
      This directly supports persistent facial edema as a rare rosacea-associated
      phenotype.
- name: Upper eyelid edema
  category: Ophthalmological
  subtype: Ocular Rosacea
  notes: >-
    Ocular rosacea can rarely present with persistent peri-orbital swelling,
    sometimes accompanied by secondary ptosis. Frequency band omitted: the sole
    source is a single case report, which establishes that the presentation
    occurs but cannot support any frequency band, not even VERY_RARE, since an
    n-of-1 report carries no denominator.
  phenotype_term:
    preferred_term: upper eyelid edema
    term:
      id: HP:0012724
      label: Upper eyelid edema
  evidence:
  - reference: PMID:41058755
    reference_title: "Unilateral Peri-Orbital Oedema and Mechanical Ptosis: An Unusual Case Presentation of Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 64-year-old Caucasian man presented with a 9-month history of persistent painless swelling of the right upper eyelid and secondary ptosis."
    explanation: >-
      This case report supports persistent upper-eyelid edema as a rare
      ocular manifestation of rosacea.
histopathology:
- name: Dermal vascular endothelial Angiopoietin 2 and Tie2 overexpression
  description: >-
    Lesional erythematotelangiectatic and papulopustular rosacea skin shows
    increased Angiopoietin 2 and Tie2 staining in endothelial cells of dermal
    vessels compared with non-lesional skin, supporting a vascular
    remodeling-associated histopathology pattern.
  context: Erythematotelangiectatic and papulopustular rosacea skin biopsies
  evidence:
  - reference: PMID:41562711
    reference_title: "Increased Expression of Angiopoietin 2 and Tie2 in Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significantly increased expression of Tie2 and Angiopoietin 2 in the endothelial cells of the dermal vessels in rosacea skin vs. non-lesional skin (100% and 33.3% for Tie2, and 100% and 50% for Angiopoietin 2) was observed."
    explanation: >-
      This provides direct biopsy-level immunohistochemical evidence for
      altered dermal vascular endothelium in rosacea lesions.
- name: Early dermal fibrotic remodeling
  finding_term:
    preferred_term: fibrosis
    term:
      id: NCIT:C3044
      label: Fibrosis
  description: >-
    Fibrotic remodeling is detectable in rosacea skin biopsies even at
    inflammation-dominant stages, indicating that tissue-remodeling changes
    begin before fully developed phymatous disease.
  context: Inflammation-dominant rosacea skin biopsies
  evidence:
  - reference: PMID:41800255
    reference_title: "Targeting Macrophage-to-Myofibroblast Transition Mitigates Progression from Inflammation to Fibrosis in Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and histological staining of skin biopsies demonstrated that fibrotic remodeling was already evident at inflammation-dominant stages"
    explanation: >-
      This study directly supports fibrosis as an observable tissue-level
      change in rosacea biopsies, not only in late rhinophyma.
- name: Sebaceous gland and surrounding soft tissue hyperplasia with fibrosis
  subtype: Phymatous Rosacea
  description: >-
    Rhinophyma shows hypertrophic remodeling of sebaceous glands and adjacent
    soft tissue accompanied by fibrosis, forming the core microscopic pattern
    of phymatous rosacea.
  context: Rhinophyma / phymatous rosacea
  evidence:
  - reference: PMID:19428039
    reference_title: "[Rhinophyma in a black African male patient]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rhinophyma is an irregular and progressive nasal hypertrophy, due to hyperplasia and fibrosis of the sebaceous glands and surrounding soft tissues."
    explanation: >-
      This abstract directly supports sebaceous gland hyperplasia with
      fibrosis as a defining microscopic tissue-remodeling feature of
      rhinophyma.
- name: Leaky vascular architecture in rhinophyma tissue
  subtype: Phymatous Rosacea
  description: >-
    Rhinophyma tissue shows an abnormal vascular architecture with leaky
    vessel profiles rather than the stromal-enveloped vascular pattern seen
    in hypertrophic scars.
  context: Rhinophyma tissue
  evidence:
  - reference: PMID:41909715
    reference_title: "Distinct diversity of skin cell populations of rhinophyma and hypertrophic scar illustrated by scRNA-seq."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vascular structures in hypertrophic scar tissues are enveloped by a significant number of stromal cells, in contrast to the leaky vascular profiles observed in rhinophyma tissues."
    explanation: >-
      This study supports a distinctive vascular tissue architecture in
      rhinophyma that fits the disease's vascular-remodeling phenotype.
- name: Immune-cell-rich rhinophyma tissue
  subtype: Phymatous Rosacea
  description: >-
    Rhinophyma tissue contains a relatively expanded immune-cell compartment,
    consistent with persistent inflammatory remodeling in phymatous disease.
  context: Rhinophyma tissue
  evidence:
  - reference: PMID:41909715
    reference_title: "Distinct diversity of skin cell populations of rhinophyma and hypertrophic scar illustrated by scRNA-seq."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the number of immune cells in rhinophyma is significantly higher than in hypertrophic scar tissues."
    explanation: >-
      This supports immune-cell enrichment as a tissue-level feature of
      rhinophyma.
- name: Eyelid tissue lymphoedema in ocular rosacea
  subtype: Ocular Rosacea
  description: >-
    In rare ocular rosacea with persistent peri-orbital swelling, eyelid
    debulking biopsy can show rosacea-associated inflammatory change with
    superimposed lymphoedematous tissue remodeling.
  context: Ocular rosacea with persistent peri-orbital edema
  evidence:
  - reference: PMID:41058755
    reference_title: "Unilateral Peri-Orbital Oedema and Mechanical Ptosis: An Unusual Case Presentation of Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathological analysis of the debulking biopsy confirmed the diagnosis of rosacea, with additional features indicative of lymphoedema."
    explanation: >-
      This provides direct biopsy-level support for lymphoedematous tissue
      change in a rare ocular rosacea presentation.
genetic:
- name: IRF1
  gene_term:
    preferred_term: IRF1
    term:
      id: hgnc:6116
      label: IRF1
  association: MR-supported druggable gene
  notes: >-
    Integrative MR/SMR analysis prioritized IRF1 as a rosacea-linked
    druggable gene and connected it to immune-cell activation and interferon
    signaling.
  evidence:
  - reference: PMID:40635520
    reference_title: "Integrated Genomic and GEO Data Analysis Reveals Therapeutic Targets for Rosacea."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "MR and SMR analyses identified IRF1 and SLC22A5 as druggable genes for rosacea, with Bayesian colocalization strongly supporting shared causal variants."
    explanation: >-
      This directly supports IRF1 as a genetically prioritized therapeutic
      target in rosacea.
- name: SLC22A5
  gene_term:
    preferred_term: SLC22A5
    term:
      id: hgnc:10969
      label: SLC22A5
  association: MR-supported druggable gene
  notes: >-
    SLC22A5 emerged from integrative MR/SMR analysis as a rosacea-linked
    druggable gene, with proposed relevance to transport and lipid
    homeostasis.
  evidence:
  - reference: PMID:40635520
    reference_title: "Integrated Genomic and GEO Data Analysis Reveals Therapeutic Targets for Rosacea."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "MR and SMR analyses identified IRF1 and SLC22A5 as druggable genes for rosacea, with Bayesian colocalization strongly supporting shared causal variants."
    explanation: >-
      This directly supports SLC22A5 as a genetically prioritized
      therapeutic target in rosacea.
- name: GZMK
  gene_term:
    preferred_term: GZMK
    term:
      id: hgnc:4711
      label: GZMK
  association: MR-supported drug target
  notes: >-
    Multi-omics prioritization identified GZMK as a rosacea-linked target and
    functionally connected it to inflammatory fibroblast activation.
  evidence:
  - reference: PMID:41139274
    reference_title: "Integrated Multi-Omics and Experimental Validation Unveil the GZMK/NF-κB Axis Driving Inflammation and Fibroblast Proliferation in Rosacea: A Novel Drug Target Selection Strategy."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "MR and colocalization identified Granzyme K (GZMK) as a drug target, whose expression increased in the affected samples."
    explanation: >-
      This supports GZMK as a genetically prioritized rosacea target with
      increased expression in disease-associated samples.
- name: MSR1
  gene_term:
    preferred_term: MSR1
    term:
      id: hgnc:7376
      label: MSR1
  association: MR-supported risk-promoting biomarker
  notes: >-
    Integrative proteomic and Mendelian-randomization analysis identified
    MSR1 as a rosacea-promoting protein target.
  evidence:
  - reference: PMID:40890957
    reference_title: "Exploring Novel Biomarkers for Rosacea Through Cohort Study and Mendelian Randomisation."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."
    explanation: >-
      This directly supports MSR1 as the risk-promoting protein among the
      final MR-prioritized rosacea biomarkers.
- name: ABHD14B
  gene_term:
    preferred_term: ABHD14B
    term:
      id: hgnc:28235
      label: ABHD14B
  association: MR-supported protective biomarker
  notes: >-
    ABHD14B was among the final proteins whose genetically informed analyses
    suggested an inhibitory relationship with rosacea onset.
  evidence:
  - reference: PMID:40890957
    reference_title: "Exploring Novel Biomarkers for Rosacea Through Cohort Study and Mendelian Randomisation."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."
    explanation: >-
      This supports ABHD14B as one of the final MR-prioritized proteins
      associated with lower rosacea risk.
- name: CHMP6
  gene_term:
    preferred_term: CHMP6
    term:
      id: hgnc:25675
      label: CHMP6
  association: MR-supported protective biomarker
  notes: >-
    CHMP6 was among the final proteins whose genetically informed analyses
    suggested an inhibitory relationship with rosacea onset.
  evidence:
  - reference: PMID:40890957
    reference_title: "Exploring Novel Biomarkers for Rosacea Through Cohort Study and Mendelian Randomisation."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."
    explanation: >-
      This supports CHMP6 as one of the final MR-prioritized proteins
      associated with lower rosacea risk.
- name: DBNL
  gene_term:
    preferred_term: DBNL
    term:
      id: hgnc:2696
      label: DBNL
  association: MR-supported protective biomarker
  notes: >-
    DBNL was among the final proteins whose genetically informed analyses
    suggested an inhibitory relationship with rosacea onset.
  evidence:
  - reference: PMID:40890957
    reference_title: "Exploring Novel Biomarkers for Rosacea Through Cohort Study and Mendelian Randomisation."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."
    explanation: >-
      This supports DBNL as one of the final MR-prioritized proteins
      associated with lower rosacea risk.
- name: MCFD2
  gene_term:
    preferred_term: MCFD2
    term:
      id: hgnc:18451
      label: MCFD2
  association: MR-supported protective biomarker
  notes: >-
    MCFD2 was among the final proteins whose genetically informed analyses
    suggested an inhibitory relationship with rosacea onset.
  evidence:
  - reference: PMID:40890957
    reference_title: "Exploring Novel Biomarkers for Rosacea Through Cohort Study and Mendelian Randomisation."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."
    explanation: >-
      This supports MCFD2 as one of the final MR-prioritized proteins
      associated with lower rosacea risk.
- name: HLA-DRA
  gene_term:
    preferred_term: HLA-DRA
    term:
      id: hgnc:4947
      label: HLA-DRA
  association: GWAS susceptibility locus (rs763035, intergenic HLA-DRA/BTNL2)
  relationship_type: SUSCEPTIBILITY
  variants:
  - name: rs763035
    identifiers:
    - dbSNP:rs763035
    description: >-
      Intergenic common variant between HLA-DRA and BTNL2; the one
      genome-wide significant SNP from the 23andMe discovery GWAS that
      replicated in an independent group.
  notes: >-
    First rosacea GWAS (23andMe; 2,618 cases/20,334 controls discovery,
    3,205/26,262 replication). The summary statistics were not deposited in
    a public repository, so this locus is recorded as gene evidence rather
    than as a dataset. Immunohistochemistry in the same study localized
    HLA-DRA protein to the perifollicular infiltrate of papulopustular
    lesions.
  evidence:
  - reference: PMID:25695682
    reference_title: "Assessment of the genetic basis of rosacea by genome-wide association study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The confirmed SNP, rs763035 (P=8.0 × 10(-11) discovery group; P=0.00031 replication group), is intergenic between HLA-DRA and BTNL2."
    explanation: >-
      Replicated genome-wide significant association placing the lead
      rosacea susceptibility variant between HLA-DRA and BTNL2.
  - reference: PMID:25695682
    reference_title: "Assessment of the genetic basis of rosacea by genome-wide association study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exploratory immunohistochemical analysis of HLA-DRA and BTNL2 expression in papulopustular rosacea lesions from six individuals, including one with the rs763035 variant, revealed staining in the perifollicular inflammatory infiltrate of rosacea for both proteins."
    explanation: >-
      Places HLA-DRA protein in the lesional inflammatory infiltrate,
      linking the locus to the immune-cell infiltration in this entry.
- name: BTNL2
  gene_term:
    preferred_term: BTNL2
    term:
      id: hgnc:1142
      label: BTNL2
  association: GWAS susceptibility locus (rs763035, intergenic HLA-DRA/BTNL2)
  relationship_type: SUSCEPTIBILITY
  notes: >-
    Shares the rs763035 lead signal with HLA-DRA (see that entry for the
    variant record). BTNL2 is a butyrophilin-like MHC-class-II-region
    immune regulator; which of the two flanking genes is the effector is
    not resolved by the association alone.
  evidence:
  - reference: PMID:25695682
    reference_title: "Assessment of the genetic basis of rosacea by genome-wide association study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The confirmed SNP, rs763035 (P=8.0 × 10(-11) discovery group; P=0.00031 replication group), is intergenic between HLA-DRA and BTNL2."
    explanation: >-
      The replicated lead SNP lies between HLA-DRA and BTNL2, so BTNL2 is
      a candidate effector gene of the locus.
  - reference: PMID:25695682
    reference_title: "Assessment of the genetic basis of rosacea by genome-wide association study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exploratory immunohistochemical analysis of HLA-DRA and BTNL2 expression in papulopustular rosacea lesions from six individuals, including one with the rs763035 variant, revealed staining in the perifollicular inflammatory infiltrate of rosacea for both proteins."
    explanation: >-
      BTNL2 protein is detected in the lesional perifollicular infiltrate.
- name: HLA-DRB1
  gene_term:
    preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  association: MHC class II risk allele HLA-DRB1*03:01
  relationship_type: SUSCEPTIBILITY
  notes: >-
    HLA-DRB1*03:01, HLA-DQB1*02:01 and HLA-DQA1*05:01 together form the
    ancestral 8.1 haplotype block; the three allele associations are not
    independent of one another.
  evidence:
  - reference: PMID:25695682
    reference_title: "Assessment of the genetic basis of rosacea by genome-wide association study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "three HLA alleles, all MHC class II proteins, were significantly associated with rosacea in the discovery group and confirmed in the replication group: HLA-DRB1*03:01 (P=1.0 × 10(-8) discovery group; P=4.4 × 10(-6) replication group)"
    explanation: >-
      Replicated association of the HLA-DRB1*03:01 allele with rosacea.
- name: HLA-DQB1
  gene_term:
    preferred_term: HLA-DQB1
    term:
      id: hgnc:4944
      label: HLA-DQB1
  association: MHC class II risk allele HLA-DQB1*02:01
  relationship_type: SUSCEPTIBILITY
  notes: >-
    Part of the DRB1*03:01-DQA1*05:01-DQB1*02:01 haplotype; see HLA-DRB1.
  evidence:
  - reference: PMID:25695682
    reference_title: "Assessment of the genetic basis of rosacea by genome-wide association study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HLA-DQB1*02:01 (P=1.3 × 10(-8) discovery group; P=7.2 × 10(-6) replication group)"
    explanation: >-
      Replicated association of the HLA-DQB1*02:01 allele with rosacea.
- name: HLA-DQA1
  gene_term:
    preferred_term: HLA-DQA1
    term:
      id: hgnc:4942
      label: HLA-DQA1
  association: MHC class II risk allele HLA-DQA1*05:01
  relationship_type: SUSCEPTIBILITY
  notes: >-
    Part of the DRB1*03:01-DQA1*05:01-DQB1*02:01 haplotype; see HLA-DRB1.
  evidence:
  - reference: PMID:25695682
    reference_title: "Assessment of the genetic basis of rosacea by genome-wide association study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HLA-DQA1*05:01 (P=1.4 × 10(-8) discovery group; P=7.6 × 10(-6) replication group)"
    explanation: >-
      Replicated association of the HLA-DQA1*05:01 allele with rosacea.
- name: IRF4
  gene_term:
    preferred_term: IRF4
    term:
      id: hgnc:6119
      label: IRF4
  association: Symptom-severity GWAS locus linked to both pigmentation and immuno-inflammatory phenotypes
  relationship_type: SUSCEPTIBILITY
  notes: >-
    Top locus in the 23andMe rosacea symptom-severity GWAS (73,265
    participants); summary statistics not publicly deposited. The IRF4
    intronic pigmentation variant rs12203592 is also a genome-wide
    significant hit in the Million Veteran Program rosacea analysis
    (GWAS Catalog GCST90476178; see the dbgap:phs001672 dataset record),
    giving independent-cohort replication of this locus.
  evidence:
  - reference: PMID:29771307
    reference_title: "Assessment of rosacea symptom severity by genome-wide association study and expression analysis highlights immuno-inflammatory and skin pigmentation genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further analyses highlighted likely gene regions or effector genes including IRF4 (P = 1.5 × 10-17), a human leukocyte antigen (HLA) region flanked by PSMB9 and HLA-DMB (P = 2.2 × 10-15), HERC2-OCA2 (P = 4.2 × 10-12), SLC45A2 (P = 1.7 × 10-10), IL13 (P = 2.8 × 10-9)"
    explanation: >-
      IRF4 is the strongest symptom-severity locus in this GWAS.
  - reference: PMID:29771307
    reference_title: "Assessment of rosacea symptom severity by genome-wide association study and expression analysis highlights immuno-inflammatory and skin pigmentation genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one has been associated with both categories (IRF4)"
    explanation: >-
      The authors classify IRF4 as bridging skin-pigmentation and
      immuno-inflammatory phenotypes.
- name: HERC2
  gene_term:
    preferred_term: HERC2
    term:
      id: hgnc:4868
      label: HERC2
  association: HERC2-OCA2 pigmentation locus associated with symptom severity
  relationship_type: SUSCEPTIBILITY
  notes: >-
    The HERC2-OCA2 region regulates OCA2 (hgnc:8101) expression and eye/skin
    pigmentation; the effector gene is not resolved by the association.
    rs12898729 at HERC2 is also genome-wide significant in the Million
    Veteran Program rosacea analysis (GWAS Catalog GCST90476178). The
    authors report the region as differentially expressed in lesional
    versus non-lesional rosacea skin.
  evidence:
  - reference: PMID:29771307
    reference_title: "Assessment of rosacea symptom severity by genome-wide association study and expression analysis highlights immuno-inflammatory and skin pigmentation genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further analyses highlighted likely gene regions or effector genes including IRF4 (P = 1.5 × 10-17), a human leukocyte antigen (HLA) region flanked by PSMB9 and HLA-DMB (P = 2.2 × 10-15), HERC2-OCA2 (P = 4.2 × 10-12), SLC45A2 (P = 1.7 × 10-10), IL13 (P = 2.8 × 10-9)"
    explanation: >-
      Genome-wide significant symptom-severity association at HERC2-OCA2.
  - reference: PMID:29771307
    reference_title: "Assessment of rosacea symptom severity by genome-wide association study and expression analysis highlights immuno-inflammatory and skin pigmentation genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genes within three loci (PSMB9-HLA-DMA, HERC-OCA2 and NRX3-DIO2) were differentially expressed in a previously published clinical rosacea transcriptomics study that compared lesional to non-lesional samples."
    explanation: >-
      Lesional expression change supports the locus acting in rosacea skin
      rather than only through constitutive pigmentation.
- name: SLC45A2
  gene_term:
    preferred_term: SLC45A2
    term:
      id: hgnc:16472
      label: SLC45A2
  association: Pigmentation gene associated with symptom severity
  relationship_type: SUSCEPTIBILITY
  notes: >-
    With HERC2-OCA2 and the near-threshold MC1R rs1805007 signal, this
    locus supports fair-skin pigmentation genetics as a component of
    rosacea susceptibility.
  evidence:
  - reference: PMID:29771307
    reference_title: "Assessment of rosacea symptom severity by genome-wide association study and expression analysis highlights immuno-inflammatory and skin pigmentation genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of these loci (HERC-OCA2 and SLC45A2) and another precedented variant (rs1805007 in melanocortin 1 receptor) with an association P value just below the significance threshold (P = 1.3 × 10-7) have been previously associated with skin phenotypes and pigmentation"
    explanation: >-
      SLC45A2 is one of the pigmentation loci reaching genome-wide
      significance for rosacea severity.
- name: IL13
  gene_term:
    preferred_term: IL13
    term:
      id: hgnc:5973
      label: IL13
  association: Immuno-inflammatory GWAS locus associated with symptom severity
  relationship_type: SUSCEPTIBILITY
  notes: >-
    Mechanistically notable alongside the Demodex node: ILC2-derived IL-13
    is the checkpoint that restrains Demodex outgrowth in mouse hair
    follicles (dataset geo:GSE197981, PMID:36044899).
  evidence:
  - reference: PMID:29771307
    reference_title: "Assessment of rosacea symptom severity by genome-wide association study and expression analysis highlights immuno-inflammatory and skin pigmentation genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further analyses highlighted likely gene regions or effector genes including IRF4 (P = 1.5 × 10-17), a human leukocyte antigen (HLA) region flanked by PSMB9 and HLA-DMB (P = 2.2 × 10-15), HERC2-OCA2 (P = 4.2 × 10-12), SLC45A2 (P = 1.7 × 10-10), IL13 (P = 2.8 × 10-9)"
    explanation: >-
      Genome-wide significant symptom-severity association at IL13.
  - reference: PMID:29771307
    reference_title: "Assessment of rosacea symptom severity by genome-wide association study and expression analysis highlights immuno-inflammatory and skin pigmentation genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two of these loci are linked to immuno-inflammation phenotypes (IL13 and PSMB9-HLA-DMA)"
    explanation: >-
      The authors classify IL13 as an immuno-inflammatory rosacea locus.
environmental:
- name: Ultraviolet B radiation
  exposure_term:
    preferred_term: exposure to ultraviolet radiation
    term:
      id: ECTO:0000006
      label: exposure to ultraviolet radiation
  influences_mechanisms:
  - target: Skin barrier dysfunction
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Ultraviolet B is listed as a favouring factor rather than a cause,
      consistent with rosacea being a chronic condition that flares rather
      than one that ultraviolet initiates. It acts on a barrier already
      compromised.
    evidence:
    - reference: PMID:34035646
      reference_title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Microorganisms, genetic predisposition, corticosteroid treatment, and ultraviolet B (UVB) radiation are favoring factors."
      explanation: >-
        Names ultraviolet B radiation among the favouring factors for this
        disease, a contributory rather than initiating role.
  description: >-
    Ultraviolet B exposure is a recognized favoring factor that can worsen
    rosacea activity and amplify inflammatory and vascular responses.
  effect: TRIGGERS
  evidence:
  - reference: PMID:34035646
    reference_title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microorganisms, genetic predisposition, corticosteroid treatment, and ultraviolet B (UVB) radiation are favoring factors."
    explanation: >-
      This review explicitly identifies UVB radiation as an important
      rosacea-promoting exposure.
- name: Corticosteroid treatment
  exposure_term:
    preferred_term: exposure to glucocorticoid
    term:
      id: ECTO:0000259
      label: exposure to glucocorticoid
  influences_mechanisms:
  - target: Skin barrier dysfunction
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      An iatrogenic exposure: topical steroids thin the skin and impair
      barrier function, producing steroid-induced rosacea and a rebound flare
      on withdrawal. Notable because the drug is sometimes given for the rash
      it worsens.
    evidence:
    - reference: PMID:34035646
      reference_title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Microorganisms, genetic predisposition, corticosteroid treatment, and ultraviolet B (UVB) radiation are favoring factors."
      explanation: >-
        Names corticosteroid treatment among the favouring factors for this
        disease, an iatrogenic contributor.
  description: >-
    Corticosteroid exposure can favor rosacea expression and is a recognized
    exacerbating factor in susceptible patients.
  effect: TRIGGERS
  evidence:
  - reference: PMID:34035646
    reference_title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microorganisms, genetic predisposition, corticosteroid treatment, and ultraviolet B (UVB) radiation are favoring factors."
    explanation: >-
      This review explicitly identifies corticosteroid treatment as a
      favoring factor for rosacea.
treatments:
- name: Trigger avoidance and photoprotection
  description: >-
    Baseline management includes avoidance of provoking exposures, gentle skin
    care, moisturization, and sun protection to reduce flares.
  role: Foundational nonpharmacologic management
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While standard measures, including avoidance of triggers, gentle cleansers, and moisturizers in combination with sun protection, may mitigate flares, control signs and symptoms in some patients"
    explanation: >-
      This review supports trigger avoidance, gentle skin care, and
      photoprotection as foundational rosacea management.
- name: Papulopustular-directed pharmacotherapy
  description: >-
    Papulopustular rosacea is commonly treated with topical metronidazole,
    azelaic acid, or ivermectin, and in more inflammatory disease with oral
    doxycycline or isotretinoin.
  role: Mainstay treatment for papulopustular disease
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metronidazole
      term:
        id: CHEBI:6909
        label: metronidazole
    - preferred_term: azelaic acid
      term:
        id: NCIT:C47407
        label: Azelaic Acid
    - preferred_term: ivermectin
      term:
        id: CHEBI:6078
        label: ivermectin
    - preferred_term: doxycycline
      term:
        id: CHEBI:50845
        label: doxycycline
    - preferred_term: isotretinoin
      term:
        id: NCIT:C603
        label: Isotretinoin
  target_mechanisms:
  - target: Demodex Folliculorum Proliferation
    treatment_effect: INHIBITS
    description: >-
      Topical acaricidal agents, including ivermectin, are used to reduce
      Demodex mite density as part of papulopustular rosacea therapy.
    evidence:
    - reference: PMID:33095403
      reference_title: "The Pathogenic Role of Demodex Mites in Rosacea: A Potential Therapeutic Target Already in Erythematotelangiectatic Rosacea?"
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "the papulopustules of rosacea can be effectively treated with topical acaricidal agents"
      explanation: >-
        Supports acaricidal treatment as effective against papulopustular
        rosacea via reduction of Demodex mite burden; ivermectin (already
        listed among this treatment's agents) has acaricidal activity, so
        the link to this specific agent is indirect rather than the source
        naming ivermectin explicitly.
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "topical metronidazole, azelaic acid, ivermectin, or oral doxycycline and isotretinoin for papulopustules of rosacea"
    explanation: >-
      This review summarizes standard pharmacologic options used for
      papulopustular rosacea.
- name: Topical brimonidine therapy
  description: >-
    Persistent background erythema can be treated with topical brimonidine to
    reduce visible vasodilatory erythema.
  role: Pharmacologic treatment for the vascular erythema phenotype
  treatment_term:
    preferred_term: topical pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: brimonidine
      term:
        id: CHEBI:3175
        label: brimonidine
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "topical brimonidine or intense pulsed light (IPL) for background persistent erythema"
    explanation: >-
      This review identifies brimonidine as a targeted therapy for
      persistent background erythema.
- name: Vascular light-based therapy
  description: >-
    Persistent vascular erythema may also be treated with light-based therapy
    such as intense pulsed light.
  role: Procedural treatment for the vascular erythema phenotype
  treatment_term:
    preferred_term: vascular light-based therapy
    term:
      id: NCIT:C15301
      label: Phototherapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic procedure
        term:
          id: NCIT:C49236
          label: Therapeutic Procedure
      value:
        preferred_term: phototherapy
        term:
          id: NCIT:C15301
          label: Phototherapy
  notes: >-
    Local OAK searches in NCIT for phototherapy, light therapy, laser
    therapy, and intense pulsed light did not return a suitable non-ionizing
    light-treatment term. This remains an NTR candidate, so the entry is
    represented with a free-text preferred term and an NCIT phototherapy
    qualifier rather than the incorrect radiotherapy term.
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "topical brimonidine or intense pulsed light (IPL) for background persistent erythema"
    explanation: >-
      This review identifies light-based vascular therapy as another
      targeted approach for persistent erythema.
- name: Cyclosporine eye drops
  description: >-
    Ocular rosacea may require targeted ophthalmic anti-inflammatory therapy
    such as cyclosporine eye drops.
  role: Pharmacologic treatment for ocular rosacea
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cyclosporine
      term:
        id: CHEBI:4031
        label: cyclosporin A
  evidence:
  - reference: PMID:28150107
    reference_title: "Acne and Rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cyclosporine eye drops for ocular rosacea"
    explanation: >-
      This review identifies cyclosporine eye drops as a treatment option
      for ocular rosacea.
- name: Morbihan disease-directed pharmacotherapy
  description: >-
    Rosacea-associated solid facial edema may require individualized
    combination pharmacotherapy centered on isotretinoin and intralesional
    corticosteroid treatment, with ketotifen used in selected refractory
    cases.
  role: Targeted treatment for rosacea-associated solid facial edema
  target_phenotypes:
  - preferred_term: facial edema
    term:
      id: HP:0000282
      label: Facial edema
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: isotretinoin
      term:
        id: NCIT:C603
        label: Isotretinoin
    - preferred_term: triamcinolone
      term:
        id: NCIT:C901
        label: Triamcinolone
    - preferred_term: ketotifen
      term:
        id: CHEBI:92511
        label: ketotifen
  evidence:
  - reference: PMID:41426892
    reference_title: "Multimodal Management of Morbihan Disease: Isotretinoin, Intralesional Triamcinolone, and Ketotifen in a Recalcitrant Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient reported partial improvement, most notably with higher isotretinoin dosing and intralesional corticosteroid injections, though intermittent flares persisted."
    explanation: >-
      This supports isotretinoin and intralesional corticosteroid treatment
      as active components of Morbihan disease management.
  - reference: PMID:41222206
    reference_title: "Unilateral presentation of Morbihan's disease: a comprehensive case report and review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Successful treatment with a series of triamcinolone injections to the upper and lower eyelids was achieved after several unsuccessful therapies."
    explanation: >-
      This independently supports intralesional triamcinolone as a useful
      treatment option for rosacea-associated solid facial edema.
- name: Laser surgical debulking for rhinophyma
  description: >-
    CO2 laser or blue-laser debulking can remove phymatous nasal tissue and
    improve function and cosmesis in selected rhinophyma.
  role: Procedural treatment for phymatous rosacea
  target_phenotypes:
  - preferred_term: rhinophyma
    term:
      id: HP:0000414
      label: Bulbous nose
  treatment_term:
    preferred_term: laser surgical procedure
    term:
      id: NCIT:C15466
      label: Laser Therapy
  evidence:
  - reference: PMID:41918801
    reference_title: "CO(2) Laser Resection of Giant Rhinophyma Under Local Anesthesia: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we emphasize the surgical value of local anesthesia with CO2 laser for rhinophyma, reducing blood loss, operation time, and the need for secondary surgery."
    explanation: >-
      This case report supports CO2 laser debulking as an effective
      rhinophyma procedure with practical operative advantages.
  - reference: PMID:40791837
    reference_title: "Rhinophyma Treatment with Blue Laser."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The use of blue laser to treat rhinophyma has shown to be an effective and safe procedure with very promising results."
    explanation: >-
      This provides additional support for laser-based debulking in
      rhinophyma.
- name: Excisional reconstruction for advanced rhinophyma
  description: >-
    Severe rhinophyma may require excision with reconstructive approaches
    such as graft-based resurfacing when tissue overgrowth is extensive.
  role: Reconstructive procedural treatment for advanced phymatous rosacea
  target_phenotypes:
  - preferred_term: rhinophyma
    term:
      id: HP:0000414
      label: Bulbous nose
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: therapeutic procedure
        term:
          id: NCIT:C49236
          label: Therapeutic Procedure
      value:
        preferred_term: skin graft
        term:
          id: NCIT:C12842
          label: Skin Graft
    - predicate:
        preferred_term: therapeutic procedure
        term:
          id: NCIT:C49236
          label: Therapeutic Procedure
      value:
        preferred_term: reconstructive surgery
        term:
          id: NCIT:C25351
          label: Reconstructive Surgery
  evidence:
  - reference: PMID:40860281
    reference_title: "Rhinophyma treated by skin graft: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surgical excision is the primary treatment, and various techniques are available."
    explanation: >-
      This supports excisional surgery as the primary treatment framework
      for advanced rhinophyma, including graft-based reconstruction.
clinical_trials:
- name: NCT01493947
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Phase III comparative topical trial of ivermectin 1% cream versus
    metronidazole 0.75% cream in papulopustular rosacea, with an extension
    period assessing relapse-related outcomes.
  target_phenotypes:
  - preferred_term: erythematous papule
    term:
      id: HP:0030350
      label: Erythematous papule
  - preferred_term: pustule
    term:
      id: HP:0200039
      label: Pustule
  evidence:
  - reference: clinicaltrials:NCT01493947
    reference_title: "Efficacy and Safety of CD5024 1% Cream Versus Metronidazole 0.75% Cream in Subjects With Papulopustular Rosacea Over 16 Weeks Treatment, Followed by a 36-week Extension Period."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To compare efficacy and safety of Ivermectin 1% cream versus metronidazole 0.75% cream in subjects with papulopustular rosacea after 16-week topical treatment."
    explanation: >-
      This registry summary supports a pivotal interventional trial focused
      on papulopustular rosacea lesion control.
- name: NCT00126399
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Phase III placebo-controlled trial of once-daily 40 mg doxycycline
    controlled-release capsules for rosacea.
  target_phenotypes:
  - preferred_term: erythematous papule
    term:
      id: HP:0030350
      label: Erythematous papule
  - preferred_term: pustule
    term:
      id: HP:0200039
      label: Pustule
  evidence:
  - reference: clinicaltrials:NCT00126399
    reference_title: "A Clinical Trial to Determine the Effects of 40 Mg Doxycycline Versus a Placebo Control for the Treatment of Rosacea"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The objective of this study is to evaluate the safety and efficacy of 40 mg doxycycline controlled-release capsules administered once daily for the treatment of rosacea compared with a placebo."
    explanation: >-
      This registry entry supports controlled clinical evaluation of
      subantimicrobial-dose doxycycline for rosacea.
- name: NCT03380390
  phase: PHASE_IV
  status: COMPLETED
  description: >-
    Phase IV open-label study of oxymetazoline 1.0% cream used adjunctively
    with energy-based therapy for persistent facial erythema in rosacea.
  target_phenotypes:
  - preferred_term: persistent centrofacial erythema
    term:
      id: HP:0001041
      label: Facial erythema
  evidence:
  - reference: clinicaltrials:NCT03380390
    reference_title: "Multicenter, Open-Label, Interventional Study on the Safety and Tolerability of Oxymetazoline and Energy-Based Therapy in Subjects With Rosacea"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study will evaluate the safety and tolerability of oxymetazoline HCl cream 1.0% when used as an adjunctive treatment to energy-based therapy for participants with moderate to severe persistent facial erythema associated with rosacea."
    explanation: >-
      This trial directly targets the persistent erythema phenotype that
      anchors erythematotelangiectatic rosacea.
- name: NCT05616923
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Early-phase vehicle-controlled trial evaluating topical MEK inhibition in
    erythematotelangiectatic rosacea.
  target_phenotypes:
  - preferred_term: persistent centrofacial erythema
    term:
      id: HP:0001041
      label: Facial erythema
  - preferred_term: flushing
    term:
      id: HP:0031284
      label: Flushing
  evidence:
  - reference: clinicaltrials:NCT05616923
    reference_title: "Topical Mitogenic-Activated Protein Kinase (MAPK) Inhibition in Rosacea"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a prospective, vehicle controlled, double blinded study to evaluate the safety and potential efficacy of a topical formulation of a MEK inhibitor in patients with erythematotelangiectatic rosacea"
    explanation: >-
      This registry entry supports a mechanism-oriented interventional study
      in the vascular erythematotelangiectatic phenotype.
animal_models:
- name: LL-37 intradermal injection mouse model
  species: Mouse
  genotype: Wild type (induced model)
  background: BALB/c
  publication: PMID:17676051
  description: >-
    Repeated intradermal injection of the rosacea-associated cathelicidin
    fragment LL-37 into mouse dorsal skin, introduced by Yamasaki et al.
    (2007) alongside SCTE/KLK5 addition and Spink5 deletion, reproduces
    erythema, leukocyte infiltration and epidermal/dermal thickening.
    Prolonged (20-day) twice-daily administration adds dermal collagen
    deposition with alpha-SMA, TNF-alpha, vimentin and COL1 induction, and
    lesions that do not fully recover. It is the standard induced model for
    TLR/LL-37, mast cell, mTORC1, NLRP3 and neurovascular studies; datasets
    geo:GSE147950 and geo:GSE308876 in this entry derive from it.
  evidence:
  - reference: PMID:17676051
    reference_title: "Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin."
    explanation: >-
      The founding description of LL-37 injection as a rosacea-like
      inflammation model.
  - reference: PMID:37185701
    reference_title: "Long-Term Administration of LL-37 Can Induce Irreversible Rosacea-like Lesion."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Balb/c mice were continuously injected intradermally with LL-37 every 12 h to induce a rosacea-like phenotype."
    explanation: >-
      Current protocol (strain, route, dosing interval) for the model.
  modeled_mechanisms:
  - target: LL-37 generation
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Exogenous LL-37 substitutes for endogenous KLK5-mediated cathelicidin
      processing, so the model enters the pathway at the LL-37 step rather
      than recapitulating its generation.
    limitations: >-
      Bypasses upstream initiation (barrier injury, TLR2 induction, KLK5
      processing); uses supraphysiological bolus dosing; dorsal murine skin
      lacks the sebaceous density and facial neurovascular anatomy of human
      centrofacial skin; no spontaneous relapse.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The TLR2 induction and KLK5 processing that generate LL-37 in human
        disease are outside the model; the peptide is supplied directly.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse dorsal skin differs from human centrofacial skin in sebaceous
        unit density, vascular and sensory-nerve anatomy, and immune
        composition.
    evidence:
    - reference: PMID:17676051
      reference_title: "Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin."
      explanation: >-
        Establishes that supplying the rosacea LL-37 peptides is sufficient
        to drive the downstream inflammation the node feeds.
  - target: Immune cell infiltration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Dermal inflammatory-cell aggregation with epidermal and dermal
      thickening after repeated LL-37 injection.
    limitations: >-
      Infiltrate composition in mouse dorsal skin has not been shown to
      match the Th1/Th17, mast cell and macrophage/dendritic profile of
      human lesions.
    readouts:
    - name: Dermal inflammatory cell aggregation on H&E
      target: Immune cell infiltration
      direction: INCREASED
      interpretation: >-
        Histological correlate of the immune infiltration node in this
        model.
      evidence:
      - reference: PMID:37185701
        reference_title: "Long-Term Administration of LL-37 Can Induce Irreversible Rosacea-like Lesion."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Haematoxylin and eosin (H&E) and Van Gieson's staining showed a high degree of inflammatory cell aggregation, thickening of the epidermis and dermis, and collagen deposition in large quantities."
        explanation: >-
          Reports the histological measurement behind this readout.
    evidence:
    - reference: PMID:37185701
      reference_title: "Long-Term Administration of LL-37 Can Induce Irreversible Rosacea-like Lesion."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Haematoxylin and eosin (H&E) and Van Gieson's staining showed a high degree of inflammatory cell aggregation, thickening of the epidermis and dermis, and collagen deposition in large quantities."
      explanation: >-
        Supports treating the model as informative for lesional immune
        infiltration.
  - target: Fibrotic dermal remodeling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Prolonged LL-37 dosing produces dermal collagen deposition with
      alpha-SMA and COL1 induction that persists after injections stop.
    limitations: >-
      Collagen deposition appears only with long-term dosing and is diffuse
      dorsal-skin fibrosis, not the sebaceous and soft-tissue hyperplasia of
      phymatous nasal disease; short-term dosing produces no fibrosis and
      fully recovers.
    readouts:
    - name: Dermal collagen deposition with alpha-SMA and COL1 induction
      target: Fibrotic dermal remodeling
      direction: INCREASED
      interpretation: >-
        Van Gieson collagen staining plus immunofluorescence/Western blot
        for myofibroblast and collagen markers.
      evidence:
      - reference: PMID:37185701
        reference_title: "Long-Term Administration of LL-37 Can Induce Irreversible Rosacea-like Lesion."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The results of immunofluorescence staining and Western blotting showed that the expression of α-SMA, TNF-α, vimentin, and COL1 in the skin of mice was significantly upregulated."
        explanation: >-
          Reports the marker measurements behind this readout.
    evidence:
    - reference: PMID:37185701
      reference_title: "Long-Term Administration of LL-37 Can Induce Irreversible Rosacea-like Lesion."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "However, rosacea-like skin lesions induced by long-term LL-37 administration did not completely recover."
      explanation: >-
        Persistence after withdrawal is what makes the model informative
        for irreversible remodeling rather than transient inflammation.
  - target: Angiogenic vascular remodeling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Long-term LL-37 induction produces dermal angiogenesis alongside
      skin thickening.
    limitations: >-
      Reported as a histological feature of the long-term protocol; the
      short-term protocol does not develop it.
    evidence:
    - reference: PMID:40296272
      reference_title: "Comparative analysis of short-term and long-term LL-37-induced rosacea-like mouse models: Histopathological features and inflammatory immune responses."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice subjected to long-term LL-37 induction developed rosacea-like pathological features, including angiogenesis, thickened skin tissue, and sebaceous gland hypertrophy."
      explanation: >-
        Angiogenesis is among the long-term model's defining features.
  - target: Sebaceous gland and soft tissue hyperplasia/fibrosis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Long-term LL-37 induction produces sebaceous gland hypertrophy with
      dermal thickening, the earliest tissue-level analogue of phymatous
      change.
    limitations: >-
      Dorsal murine sebaceous hypertrophy is not nasal rhinophyma; the
      model lacks the human nose's sebaceous density and the decades-long
      course over which phyma develops.
    evidence:
    - reference: PMID:40296272
      reference_title: "Comparative analysis of short-term and long-term LL-37-induced rosacea-like mouse models: Histopathological features and inflammatory immune responses."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice subjected to long-term LL-37 induction developed rosacea-like pathological features, including angiogenesis, thickened skin tissue, and sebaceous gland hypertrophy."
      explanation: >-
        Sebaceous gland hypertrophy appears only with prolonged induction,
        matching the late position of phymatous change in the pathograph.
- name: Facial LL-37 injection mouse model with trigeminal readouts
  species: Mouse
  genotype: Wild type (induced model)
  publication: PMID:36517318
  description: >-
    A variant of the LL-37 model in which the peptide is injected
    intradermally into the face rather than the dorsum, so that lesions
    form in facial skin innervated by the trigeminal ganglion. Used to study
    the sensory symptoms of rosacea: facial injection produced rosacea-like
    lesions together with pruritus-indicative behaviour, and the
    temperature-sensitive channels TRPV4 and TRPM8 were increased in both
    the lesional skin and the trigeminal ganglion, matching increases in
    human rosacea skin. This is the only rodent model in this entry that
    uses the facial site and its native sensory innervation.
  evidence:
  - reference: PMID:36517318
    reference_title: "The temperature-sensitive receptors TRPV4 and TRPM8 have important roles in the pruritus of rosacea."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The LL-37 was injected intradermally into the face of mice to establish the animal model."
    explanation: >-
      Defines the facial-site variant of the LL-37 model.
  - reference: PMID:36517318
    reference_title: "The temperature-sensitive receptors TRPV4 and TRPM8 have important roles in the pruritus of rosacea."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Intradermal injection of LL-37 not only caused rosacea-like facial lesions but also induced a behavioural pattern indicative of pruritus."
    explanation: >-
      Facial lesions plus a sensory-symptom readout.
  modeled_mechanisms:
  - target: TRP and neuropeptide signaling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Facial LL-37 lesions are accompanied by increased TRPV4 and TRPM8 in
      skin and in the trigeminal ganglion, with pruritus behaviour, so the
      model reports the sensory-neuron arm of the neurovascular program at
      its anatomically correct site.
    limitations: >-
      Reports itch-related TRPV4/TRPM8 rather than the TRPV1/TRPA1-CGRP
      axis usually invoked for flushing and burning; behavioural pruritus
      scoring in mice is an indirect proxy for human sensory symptoms;
      mouse facial skin still differs from human centrofacial skin in
      sebaceous and vascular density.
    readouts:
    - name: TRPV4 and TRPM8 expression in lesional facial skin and trigeminal ganglion
      target: TRP and neuropeptide signaling
      direction: INCREASED
      interpretation: >-
        Transcript and protein increase of temperature-sensitive TRP
        channels in the skin and its sensory ganglion, paralleled in human
        rosacea skin samples.
      evidence:
      - reference: PMID:36517318
        reference_title: "The temperature-sensitive receptors TRPV4 and TRPM8 have important roles in the pruritus of rosacea."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Increased expression of the temperature-sensitive receptors TRPV4 and TRPM8 was found in pruritic mouse skin and TG and human skin samples."
        explanation: >-
          Reports the measurement behind this readout in both model and
          human tissue.
    evidence:
    - reference: PMID:36517318
      reference_title: "The temperature-sensitive receptors TRPV4 and TRPM8 have important roles in the pruritus of rosacea."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Increased expression of the temperature-sensitive receptors TRPV4 and TRPM8 was found in pruritic mouse skin and TG and human skin samples."
      explanation: >-
        Supports treating the facial model as informative for TRP-channel
        sensory signaling.
- name: Demodex mite injection rabbit model
  species: Rabbit
  genotype: Wild type (induced model)
  background: Japanese rabbit
  publication: PMID:36177392
  description: >-
    Intradermal injection of a suspension of Demodex mites into rabbit
    skin, followed over four weeks. Erythematous papules appear by the
    second week, with foreign-body material, telangiectasia and then an
    organized granuloma-like structure on histology, mimicking the lesions
    and histopathology of Demodex-positive rosacea. The only model in this
    entry in which the mite itself is the perturbation in vivo.
  evidence:
  - reference: PMID:36177392
    reference_title: "Development of an animal model for rosacea‑like skin lesions caused by Demodex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the model of Demodex-induced rosacea-like skin lesions can be developed through intradermal injection of suspension of Demodex mites into Japanese rabbits."
    explanation: >-
      Defines the model.
  - reference: PMID:36177392
    reference_title: "Development of an animal model for rosacea‑like skin lesions caused by Demodex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The model can mimic the phenotype of skin lesions and histopathological manifestations in the Demodex mite-positive patient with rosacea."
    explanation: >-
      The authors' statement of what the model reproduces.
  modeled_mechanisms:
  - target: Demodex Folliculorum Proliferation
    relationship: PERTURBS
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      A bolus of injected mites stands in for follicular mite
      proliferation, so the model perturbs the Demodex node rather than
      reproducing gradual pilosebaceous colonization.
    limitations: >-
      Injected mite suspension bypasses follicular residence and the
      sebocyte interface where Demodex acts in humans; the resulting
      foreign-body and granulomatous reaction is a stronger stimulus than
      commensal overgrowth; rabbit skin is not sebaceous facial skin.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        Follicular colonization and mite-sebocyte interaction, the events
        this node describes, are outside the model; mites are delivered
        directly into the dermis.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Rabbit skin lacks the sebaceous-rich centrofacial architecture in
        which human Demodex proliferation occurs.
    evidence:
    - reference: PMID:36177392
      reference_title: "Development of an animal model for rosacea‑like skin lesions caused by Demodex."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the model of Demodex-induced rosacea-like skin lesions can be developed through intradermal injection of suspension of Demodex mites into Japanese rabbits."
      explanation: >-
        The mite is the applied perturbation.
  - target: Papulopustular inflammation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Mite injection produces erythematous papules and telangiectasia with
      a granuloma-like histology.
    limitations: >-
      The lesion is granulomatous around foreign mite material rather than
      the neutrophilic follicular pustule of human papulopustular rosacea;
      no pustules are reported.
    readouts:
    - name: Erythematous papules, telangiectasia and granuloma-like structure on H&E
      target: Papulopustular inflammation
      direction: INCREASED
      interpretation: >-
        Sequential clinical and histological lesion development over four
        weeks.
      evidence:
      - reference: PMID:36177392
        reference_title: "Development of an animal model for rosacea‑like skin lesions caused by Demodex."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Lumpy foreign bodies, telangiectasia and granuloma-like structure were observed in the model rabbit in the 1st, 2nd, and 3rd weeks, respectively."
        explanation: >-
          Reports the histological readouts and their timing.
    evidence:
    - reference: PMID:36177392
      reference_title: "Development of an animal model for rosacea‑like skin lesions caused by Demodex."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Erythema papules were observed in the model rabbit skin and could be observed most clearly in the 2nd week."
      explanation: >-
        Supports the model as informative for the papular lesion, with the
        granulomatous caveat above.
experimental_models:
- name: Paired lesional and non-lesional papulopustular rosacea skin explants
  experimental_model_type: OTHER
  description: >-
    Ex vivo full-thickness facial skin explants taken as paired lesional and
    non-lesional biopsies from papulopustular rosacea patients, cultured
    with or without IL-1beta and profiled by RNA-seq and by two proteomic
    platforms (dataset geo:GSE155141 in this entry). The explant keeps the
    resident multicellular circuit intact (keratinocytes, fibroblasts,
    mast cells, vessels and infiltrating immune cells), so it is the one
    human system that contains the fibroblast-centred network described
    by single-cell profiling, and the paired design controls for donor.
    The only NAM here that is human facial skin.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: facial skin explant
    term:
      id: UBERON:1000021
      label: skin of face
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: dermal fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: mast cell
    term:
      id: CL:0000097
      label: mast cell
  conditions:
  - lesional papulopustular rosacea explant
  - paired non-lesional explant
  - IL-1beta-treated non-lesional explant
  culture_system: >-
    Ex vivo explant culture of paired human biopsies, untreated or
    stimulated with recombinant IL-1beta; transcriptome by Illumina RNA-seq
    in duplicate, proteome by MSD and Olink panels.
  modeled_mechanisms:
  - target: Papulopustular inflammation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: >-
      Lesional explants carry the in vivo papulopustular inflammatory
      program into culture; MAPK and TNF signaling are the most up-regulated
      pathways versus paired non-lesional tissue.
    limitations: >-
      Explants survive days, not the chronic relapsing course; there is no
      perfusion, no recruitment of circulating leukocytes and no sensory
      innervation, so the tissue reports the established lesion rather than
      its initiation or its neurovascular symptoms.
    readouts:
    - name: Lesional versus non-lesional pathway enrichment (MAPK, TNF)
      target: Papulopustular inflammation
      direction: INCREASED
      interpretation: >-
        Transcriptomic and proteomic pathway activity of the lesion,
        measured against the same donor's uninvolved skin.
      evidence:
      - reference: GEO:GSE155141
        reference_title: "Paired transcriptomic and proteomic analysis implicates IL-1β in the pathogenesis of papulopustular rosacea explants [RNA-seq]"
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Our study suggests that MAPK and TNF signaling pathways are the most significantly upregulated pathways in lesional papulopustular rosacea human skins, highlighting IL-1β as a potential central mediator."
        explanation: >-
          Reports the pathway readout measured in the explant system.
    evidence:
    - reference: GEO:GSE155141
      reference_title: "Paired transcriptomic and proteomic analysis implicates IL-1β in the pathogenesis of papulopustular rosacea explants [RNA-seq]"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The goal of this study is to utilize human papulopustular rosacea biopsy explants to integrate both differentially expressed genes and differently expressed proteins in paired non-lesional and lesional papulopustular rosacea tissues."
      explanation: >-
        Defines the explant system and its paired lesional design.
  - target: NLRP3 Inflammasome Activation
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Exogenous IL-1beta applied to non-lesional explants perturbs the
      IL-1 arm downstream of the inflammasome; the dataset-analysis run on
      this series found IL-1beta induces NLRP3 transcription in
      non-lesional tissue while the inflammasome module is not elevated at
      steady state in lesional explants.
    limitations: >-
      IL-1beta is the inflammasome's product, not its trigger, so the
      perturbation tests feed-forward priming rather than LL-37-driven
      inflammasome assembly; five donor pairs limit power, and the priming
      effect did not survive FDR correction.
    readouts:
    - name: NLRP3 transcript after IL-1beta treatment of non-lesional explants
      target: NLRP3 Inflammasome Activation
      direction: INCREASED
      interpretation: >-
        Feed-forward priming of NLRP3 by IL-1beta in human skin; nominal
        paired p = 0.025 in the KB's own re-analysis, see notes.
    evidence:
    - reference: GEO:GSE155141
      reference_title: "Paired transcriptomic and proteomic analysis implicates IL-1β in the pathogenesis of papulopustular rosacea explants [RNA-seq]"
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Our study suggests that MAPK and TNF signaling pathways are the most significantly upregulated pathways in lesional papulopustular rosacea human skins, highlighting IL-1β as a potential central mediator."
      explanation: >-
        The series' own conclusion places IL-1beta centrally; the link to
        the inflammasome node is by inference from the IL-1beta arm.
  notes: >-
    The NLRP3 readout comes from the assessed dataset-analysis run in
    kb/hypotheses/Rosacea/ll37_nlrp3_il1b_papulopustular/, not from a
    publication; no PubMed record is linked to GSE155141 at time of
    curation, so the GEO summary is the citable source.
- name: SZ95 sebocyte and live Demodex mite co-culture
  experimental_model_type: CO_CULTURE
  description: >-
    Immortalized human SZ95 sebocytes co-cultured with live Demodex mites
    extracted from normal facial skin, or exposed to mite-conditioned
    medium, in time- and mite-dose-dependent experiments with Toll-like
    receptor pathway gene and protein readouts. The only system in which
    the mite is the applied perturbation against a human sebaceous cell,
    the compartment where Demodex lives in vivo.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: SZ95 sebocyte
    term:
      id: CL:0000317
      label: sebocyte
  conditions:
  - SZ95 sebocytes with live Demodex mites (low and high mite numbers)
  - SZ95 sebocytes with Demodex-conditioned medium
  - untreated SZ95 sebocytes
  culture_system: >-
    Immortalized SZ95 sebocyte line; live mites or mite-conditioned medium;
    TLR-pathway expression by RT-PCR array and protein assays; cytokine
    secretion by ELISA over a 48-hour time course.
  publication: PMID:29532463
  modeled_mechanisms:
  - target: Demodex Folliculorum Proliferation
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Mite number is the controlled input, so the system tests what a
      rising mite load does to the sebocyte rather than reproducing
      follicular proliferation itself.
    limitations: >-
      Mites came from normal donors and were applied to a monoculture with
      no follicular architecture, keratinocytes or immune cells; the TLR
      response was biphasic (early down-modulation, up-regulation after
      48 h), so single-time-point readouts can mislead.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The follicle, its keratinocytes and the immune cells that respond to
        mite-derived signals in vivo are outside the model; only the
        sebocyte's own response is observed.
    readouts:
    - name: Interleukin-8 secretion versus mite number
      target: Demodex Folliculorum Proliferation
      direction: INCREASED
      interpretation: >-
        Mite-load-dependent pro-inflammatory cytokine output from
        sebocytes; low numbers did not induce it.
      evidence:
      - reference: PMID:29532463
        reference_title: "Demodex mites modulate sebocyte immune reaction: possible role in the pathogenesis of rosacea."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "High numbers of Demodex induced proinflammatory cytokine secretion, whereas lower numbers did not."
        explanation: >-
          Reports the dose-dependent cytokine readout.
    evidence:
    - reference: PMID:29532463
      reference_title: "Demodex mites modulate sebocyte immune reaction: possible role in the pathogenesis of rosacea."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Live Demodex mites were extracted from normal facial skin of control subjects and used in cell stimulation experiments with the immortalized SZ95 sebocyte line."
      explanation: >-
        Defines the model and its mite-as-input design.
  - target: TLR2 upregulation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Mite-secreted molecules change TLR2 receptor expression in sebocytes,
      the cell-type-specific counterpart of the keratinocyte TLR2 rise the
      node describes.
    limitations: >-
      Sebocytes, not keratinocytes; the direction of TLR-pathway change
      reversed between early and 48-hour time points, so this is a
      modulation rather than a clean sustained up-regulation.
    readouts:
    - name: TLR2 receptor expression in sebocytes after mite exposure
      target: TLR2 upregulation
      direction: ALTERED
      interpretation: >-
        Bidirectional, time-dependent change in TLR2 expression driven by
        secreted mite factors.
      evidence:
      - reference: PMID:29532463
        reference_title: "Demodex mites modulate sebocyte immune reaction: possible role in the pathogenesis of rosacea."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Demodex secreted bioactive molecules that affected TLR2 receptor expression by sebocytes."
        explanation: >-
          Reports the TLR2 expression readout.
    evidence:
    - reference: PMID:29532463
      reference_title: "Demodex mites modulate sebocyte immune reaction: possible role in the pathogenesis of rosacea."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Mites modulated TLR signalling events on both mRNA and protein levels in SZ95 sebocytes."
      explanation: >-
        Supports the model as informative for TLR-pathway modulation.
  - target: Sebaceous gland dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Shows that the sebocyte is an immune-reactive participant that mites
      can push into cytokine production, one component of sebaceous-unit
      dysfunction.
    limitations: >-
      Immune reactivity only; sebum lipid output, gland morphology and the
      hyperplastic changes of phyma are not measured.
    evidence:
    - reference: PMID:29532463
      reference_title: "Demodex mites modulate sebocyte immune reaction: possible role in the pathogenesis of rosacea."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Mites have the capacity to secrete bioactive molecules that affect the immune reactivity of sebocytes."
      explanation: >-
        Supports sebocyte immune reactivity as the modelled aspect of
        sebaceous-unit dysfunction.
- name: HaCaT keratinocytes under simulated rosacea conditions
  experimental_model_type: CELL_LINE
  description: >-
    Immortalized human HaCaT keratinocytes exposed to conditions simulating
    the rosacea inflammatory milieu, read out by RT-qPCR, western blot,
    ELISA and scratch and Transwell assays. Used to test whether the
    inflammatory gene program seen in patient transcriptomes is
    reproducible in keratinocytes and to screen candidate drugs. The
    publication describes the stimulus only as simulated rosacea
    conditions, so no specific trigger is asserted here.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: HaCaT keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  conditions:
  - HaCaT cells under simulated rosacea conditions
  - untreated HaCaT cells
  culture_system: >-
    Immortalized HaCaT keratinocyte monolayer; gene and protein expression
    by RT-qPCR, western blot and ELISA; proliferation and migration by
    scratch and Transwell assays.
  publication: PMID:39823143
  modeled_mechanisms:
  - target: TLR2 upregulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Keratinocyte TLR2 and S100A9 protein rise under the simulated rosacea
      milieu, matching the lesional TLR2 increase in patient skin.
    limitations: >-
      An immortalized, spontaneously transformed keratinocyte line in
      monoculture with no barrier stratification, sebaceous or immune
      component; the stimulus is not characterized in the abstract.
    readouts:
    - name: TLR2 and S100A9 protein expression
      target: TLR2 upregulation
      direction: INCREASED
      interpretation: >-
        Protein-level induction of the innate receptor and its alarmin
        partner in stimulated keratinocytes.
      evidence:
      - reference: PMID:39823143
        reference_title: "Unveiling the Molecular Mechanisms of Rosacea: Insights From Transcriptomics and In Vitro Experiments."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Specifically, Toll-like receptor 2 (TLR2) and S100A9 proteins were upregulated, potentially promoting these processes."
        explanation: >-
          Reports the TLR2/S100A9 protein readout.
    evidence:
    - reference: PMID:39823143
      reference_title: "Unveiling the Molecular Mechanisms of Rosacea: Insights From Transcriptomics and In Vitro Experiments."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In vitro, HaCaT cells exhibited enhanced proliferation and migration abilities, accompanied by increased expression of pro-inflammatory genes and proteins."
      explanation: >-
        Supports the keratinocyte model as reproducing the inflammatory
        program in which TLR2 rises.
computational_models:
- name: Rosacea Innate-Immune Axis Boolean Model
  description: >-
    A synchronous Boolean network of the cutaneous innate-immune arm of
    rosacea: barrier impairment and Demodex proliferation through
    pro-cathelicidin transcription, TLR2, KLK5/KLK7 and LL-37 to the
    inflammasome, mast-cell, Th1/Th17 and angiogenic branches, and on to the
    vascular and papulopustular phenotypes. Authored in this repository
    rather than curated from a publication, because no Boolean, logical or
    other dynamical model of rosacea has been published; PubMed returns
    nothing for rosacea combined with Boolean network, logical model,
    agent-based or mathematical model, and the computational rosacea
    literature is entirely network pharmacology and molecular docking.
    Every node maps to a pathophysiology, environmental, treatment or
    phenotype node in this entry, and every rule transcribes causal edges
    curated here, so the model asserts no biology of its own: it makes the
    curated chain executable, so that what the chain implies can be derived
    instead of argued. Nothing in it is fitted to data.
  model_type: BOOLEAN_NETWORK
  model_id: rosacea_innate_boolean
  model_format: Boolean rule specification (YAML)
  model_software: Python (standard library and PyYAML)
  findings:
  - statement: >-
      No combination of the interventions that can be grounded in this entry
      switches off the papulopustular phenotype in the model.
    supporting_text: >-
      Papulopustular inflammation is driven by three curated edges in
      parallel (inflammasome, immune-cell infiltration, Th1/Th17), and the
      immune-infiltration arm is fed by barrier dysfunction through STAT3,
      by fibroblast expansion and by the ACSL5 node. The entry curates
      exactly one treatment-to-mechanism edge, acaricidal therapy onto the
      Demodex node, so nothing in the model acts on that arm. This is a
      statement about the entry's treatment curation, not about whether
      rosacea is treatable: the several treatments curated here without a
      target_mechanisms link are invisible to the model.
  - statement: >-
      Removing mites alone clears only telangiectasia in the model, which
      overstates what an acaricide does to the cathelicidin axis.
    supporting_text: >-
      Demodex proliferation is the only curated upstream cause of TLR2
      upregulation in this entry, so switching it off removes TLR2, KLK5/KLK7
      and therefore all of LL-37's branches. Ultraviolet exposure and barrier
      impairment are curated onto pro-cathelicidin transcription but not onto
      TLR2, so the model cannot generate LL-37 without mites. The gap is in
      the curated graph, not in the biology, and it is the clearest curation
      lead the model produces.
  - statement: >-
      The erythematotelangiectatic scenario produces papules and pustules,
      which is clinically wrong and exposes the absence of subtype gating in
      the curated graph.
    supporting_text: >-
      With mites off but barrier, fibroblast and ACSL5 inputs on, the
      immune-infiltration arm still fires and the papulopustular node with
      it. The curated edges carry no subtype conditionality, and the model
      inherits that: it cannot represent a vascular-predominant phenotype
      without papulopustular lesions. The same scenario also produces the
      mirror-image error, and it is the sharper one: telangiectasia is
      false in a scenario named for it, because the only curated route to
      angiogenic remodeling runs through LL-37, and LL-37 cannot be made
      without mites. The subtype the model handles worst is the one whose
      defining sign it cannot generate. Both are limitations of the
      encoding, not predictions.
  modeled_mechanisms:
  - target: Papulopustular inflammation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      The node is reproduced as the disjunction of its three curated
      upstream edges, so the model reproduces which arms can produce the
      lesion but not how much of each is needed, nor its time course.
    limitations: >-
      Binary activity with synchronous update: no dose, no kinetics, no
      threshold behaviour and no partial response. Treating the three
      upstream edges as independently sufficient is the least safe
      assumption in the model; if lesion formation actually requires several
      arms together, the single-agent results are optimistic.
    divergences:
    - divergence_type: STRUCTURAL_IDEALIZATION
      materiality: QUALIFYING
      description: >-
        Each mechanism is one on/off node updated synchronously. Graded
        processes such as mite density, cathelicidin concentration and
        infiltrate magnitude, all quantitative in the cited sources, become
        binary, so the model cannot express severity or partial treatment
        response.
    - divergence_type: CALIBRATION_PROVENANCE
      materiality: QUALIFYING
      description: >-
        Nothing is calibrated. The rules are a transcription of curated
        edges, and no parameter, threshold or weight is fitted to any
        dataset, including the transcriptomic series curated in this entry.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The ocular chain (meibomian gland dysfunction, ocular surface
        inflammation, blepharitis) and the phymatous chain (sebaceous gland
        dysfunction, hyperplasia and fibrosis, phymatous change) are outside
        the model, as are the fibrotic-remodeling and gut-skin-axis nodes.
    - divergence_type: SCALE_EXTRAPOLATION
      materiality: QUALIFYING
      description: >-
        What the network computes is the on/off state of signalling and
        cell-population rules; the lesion is a tissue-scale outcome that the
        model reaches only by naming an output node after it. The node
        Papulopustular_inflammation is a logical consequence of its three
        upstream rules, not a simulated tissue.
    readouts:
    - name: Papulopustular_inflammation node state across the intervention scan
      target: Papulopustular inflammation
      direction: UNCHANGED
      interpretation: >-
        The node stays active under every single and paired combination of
        the three encodable interventions, because none of them acts on the
        immune-infiltration arm.
  - target: Neurovascular vasodilation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Reproduced as the disjunction of its three curated upstream edges
      (mast-cell amplification, fibroblast expansion, TRP and neuropeptide
      signaling), gated by topical brimonidine.
    limitations: >-
      TRP and neuropeptide signaling is an input rather than a computed
      node, because the entry curates no upstream cause for it, so the model
      cannot represent a trigger-driven flush. Brimonidine's target is
      inferred from its treatment description, since it carries no curated
      target_mechanisms edge.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: INVALIDATING
      description: >-
        The triggers that actually drive flushing (heat, alcohol, spicy food,
        emotional stress) are not curated in this entry and so are not in the
        model. For the flushing phenotype specifically the model is a
        placeholder: its vasodilation node can only be switched by inputs
        that are asserted, never provoked.
    - divergence_type: SCALE_EXTRAPOLATION
      materiality: QUALIFYING
      description: >-
        Vessel calibre is a tissue-scale property. The model computes only
        whether a vasodilation rule evaluates true from its three upstream
        cell-level inputs, so the tissue outcome is inferred from the rule,
        never represented.
    readouts:
    - name: Flushing node state under brimonidine
      target: Neurovascular vasodilation
      direction: DECREASED
      interpretation: >-
        Brimonidine clears the flushing output but leaves persistent
        erythema active, because erythema is additionally fed by the
        angiogenic-remodeling branch.
  notes: >-
    Spec models/rosacea_innate_boolean.yaml, runner
    models/rosacea_innate_boolean.py, committed results
    models/rosacea_innate_boolean.results.json. Regenerate with
    `uv run python models/rosacea_innate_boolean.py`; `--check` fails if the
    committed results are stale and `--print` shows the summary. The runner
    is deterministic, uses only the standard library and PyYAML, and parses
    the rule language rather than calling eval. NOT wired to dismech-perturb
    and deliberately given no models/rosacea_innate_boolean.config.yaml:
    that runner executes SBML through tellurium and cannot run a logical
    network, so the model is correctly reported as not runnable in-repo by
    the models browser. The spec records, per rule, which curated edges it
    encodes and which Boolean choices (the AND at LL-37 generation, the ORs
    elsewhere) the edge list did not itself determine.
datasets:
- accession: geo:GSE65914
  title: Th1/Th17 Immune Response in Rosacea
  description: >-
    Human facial biopsy transcriptomic dataset spanning rosacea subtypes and
    healthy controls, used to define adaptive immune and inflammatory cell
    programs across erythematotelangiectatic, papulopustular, and phymatous
    disease.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 58
  conditions:
  - erythematotelangiectatic rosacea
  - papulopustular rosacea
  - phymatous rosacea
  - healthy control facial skin
  publication: PMID:25848978
  evidence:
  - reference: GEO:GSE65914
    reference_title: "Th1/Th17 Immune Response in Rosacea"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The T cell response is dominated by Th1/Th17-polarized immune cells, as demonstrated by significant upregulation of IFNγ or IL-17, for example."
    explanation: >-
      This GEO series directly supports subtype-spanning adaptive immune
      polarization in human rosacea tissue.
- accession: geo:GSE155141
  title: Paired transcriptomic and proteomic analysis implicates IL-1β in the pathogenesis of papulopustular rosacea explants [RNA-seq]
  description: >-
    Human RNA-seq dataset from paired non-lesional and lesional
    papulopustular rosacea explants, linked to paired proteomic profiling and
    inflammatory pathway analysis.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 15
  conditions:
  - non-lesional papulopustular rosacea skin
  - lesional papulopustular rosacea skin
  - IL-1beta-treated non-lesional rosacea skin
  publication: PMID:32941918
  evidence:
  - reference: GEO:GSE155141
    reference_title: "Paired transcriptomic and proteomic analysis implicates IL-1β in the pathogenesis of papulopustular rosacea explants [RNA-seq]"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our study suggests that MAPK and TNF signaling pathways are the most significantly upregulated pathways in lesional papulopustular rosacea human skins, highlighting IL-1β as a potential central mediator."
    explanation: >-
      This dataset captures lesion-associated inflammatory pathway activity
      in papulopustular rosacea. Graded IN_VITRO because the profiled
      material is cultured ex vivo biopsy explants, which this repository
      classes as in vitro, matching the sibling in vitro keratinocyte
      dataset geo:GSE303282.
- accession: geo:GSE303282
  title: Cathelicidin LL-37-induced transcriptome of human keratinocyte identifies chemokine CXCL10 link to T cell-mediated rosacea pathogenesis via JAK-1/STAT-1 pathway
  description: >-
    Human keratinocyte microarray dataset modeling LL-37-driven rosacea-like
    inflammation in vitro to resolve chemokine and JAK-STAT signaling outputs
    downstream of cathelicidin exposure.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 6
  conditions:
  - LL-37-treated primary keratinocytes
  - untreated primary keratinocytes
  evidence:
  - reference: GEO:GSE303282
    reference_title: "Cathelicidin LL-37-induced transcriptome of human keratinocyte identifies chemokine CXCL10 link to T cell-mediated rosacea pathogenesis via JAK-1/STAT-1 pathway"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mechanistically, LL-37 induced CXCL10 production relied on JAK-1/STAT-1 signaling pathway."
    explanation: >-
      This in vitro transcriptomic dataset is directly relevant to the
      cathelicidin and STAT-linked mechanism nodes in rosacea.
- accession: geo:GSE277020
  title: Effect of eyelid UVB irradiation on gene expression of rat meibomian gland
  description: >-
    Rat bulk RNA-seq dataset from a UVB-induced ocular rosacea model focused
    on meibomian gland dysfunction, ocular surface injury, and downstream
    inflammatory and keratinization pathways.
  organism:
    preferred_term: Rattus norvegicus
    term:
      id: NCBITaxon:10116
      label: Rattus norvegicus
  data_type: BULK_RNA_SEQ
  sample_count: 7
  conditions:
  - UVB-irradiated rat eyelids and meibomian glands
  - non-irradiated rat controls
  evidence:
  - reference: GEO:GSE277020
    reference_title: "Effect of eyelid UVB irradiation on gene expression of rat meibomian gland"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We have developed a rat model of UVB-induced ocular surface and eyelid damages mimicking ocular rosacea, a common chronic inflammatory and neurovascular ocular surface disease associated with meibomian gland dysfunction."
    explanation: >-
      This dataset provides an ocular/meibomian model aligned to the ocular
      rosacea subgraph in this entry.
- accession: geo:GSE147950
  title: A positive feedback circuit between mTORC1 signaling and cathelicidin promotes skin inflammation in rosacea [mouse]
  description: >-
    Mouse bulk RNA-seq from an LL-37-induced rosacea-like skin model, with
    and without rapamycin, used to define the mTORC1-cathelicidin positive
    feedback loop that amplifies cutaneous inflammation. Aligns with the
    cathelicidin/LL-37 arm of the pathograph.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 12
  conditions:
  - rosacea-like mouse skin lesions
  - control mouse skin
  - rapamycin-treated skin
  publication: PMID:33734592
  evidence:
  - reference: GEO:GSE147950
    reference_title: "A positive feedback circuit between mTORC1 signaling and cathelicidin promotes skin inflammation in rosacea [mouse]"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The goal of this study is to figure out the role of mTORC1 signaling in the pathogenesis of rosacea by comparing rosacea mouse model skin lesion transcriptome profiling (RNA-seq) to that of control mouse skin treated with or without rapamycin."
    explanation: >-
      GEO summary establishes this as a rosacea mouse-model transcriptome
      designed to interrogate mTORC1 signaling, a regulator upstream of the
      cathelicidin pathway modeled in this entry.
- accession: geo:GSE308876
  title: Dorsal Root Ganglion-Mediated Modulation of Neuroinflammation and Neurovasodilation in Rosacea by Gabapentin
  description: >-
    Mouse bulk RNA-seq of skin and dorsal root ganglia from an LL-37-induced
    rosacea model treated with gabapentin, profiling neuroimmune and
    neurovascular activation (CGRP, nitric oxide synthases) and its
    suppression. Aligns with the TRP/neuropeptide and neurovascular
    vasodilation nodes.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 24
  conditions:
  - LL-37-induced rosacea-like mouse skin
  - LL-37-induced rosacea-like mouse dorsal root ganglia
  - gabapentin-treated skin and dorsal root ganglia
  evidence:
  - reference: GEO:GSE308876
    reference_title: "Dorsal Root Ganglion-Mediated Modulation of Neuroinflammation and Neurovasodilation in Rosacea by Gabapentin"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "LL37 triggered parallel neuroimmune and neurovascular activation in skin and DRG, including upregulating of Th2, IGF, CGRP, and nitric oxide synthases."
    explanation: >-
      GEO summary documents neuropeptide (CGRP) and nitric oxide synthase
      induction in the LL-37 rosacea model, the neurovascular program this
      entry models.
  notes: >-
    No linked publication is listed on the GEO record at time of curation.
- accession: geo:GSE291177
  title: RNAseq of Mineralocorticoid Receptor (MR) overexpression in UVB-induced ocular rosacea model on meibomian glands of rats
  description: >-
    Rat meibomian-gland bulk RNA-seq from the UVB-induced ocular rosacea
    model, comparing wild-type animals with rats overexpressing the human
    mineralocorticoid receptor. Companion to GSE277020 from the same model
    and aligned to the meibomian gland dysfunction node.
  organism:
    preferred_term: Rattus norvegicus
    term:
      id: NCBITaxon:10116
      label: Rattus norvegicus
  data_type: BULK_RNA_SEQ
  sample_count: 17
  conditions:
  - UVB-irradiated wild-type rat meibomian glands
  - UVB-irradiated mineralocorticoid-receptor-overexpressing rat meibomian glands
  - non-irradiated wild-type and transgenic controls
  evidence:
  - reference: GEO:GSE291177
    reference_title: "RNAseq of Mineralocorticoid Receptor (MR) overexpression in UVB-induced ocular rosacea model on meibomian glands of rats"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The aim of this study was to analyse the transcriptional regulation of UVB-induced ocular rosacea model on the meibomian glands of rats that overexpress the human NRC32 gene coding for mineralocorticoid receptor (P1.hMR) and age- and sex- matched wild type (WT) littlemates."
    explanation: >-
      GEO summary identifies this as a meibomian-gland transcriptome from
      the UVB ocular rosacea model, matching the ocular subgraph.
  notes: >-
    No linked publication is listed on the GEO record at time of curation.
- accession: geo:GSE268986
  title: Agonism of the glutamate receptor GluK2 suppresses dermal mast cell activation and cutaneous inflammation
  description: >-
    Mouse mast-cell transcriptomic dataset from a study of GluK2 agonism
    (SYM2081) as a suppressor of MrgprB2-driven mast cell activation, with
    in vivo validation in murine dermatitis and rosacea models. Aligns with
    the mast cell-mediated amplification node; rosacea is one of two disease
    models in the study, not its sole focus.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 12
  conditions:
  - SYM2081-treated mast cells
  - vehicle-treated mast cells
  publication: PMID:39661706
  evidence:
  - reference: GEO:GSE268986
    reference_title: "Agonism of the glutamate receptor GluK2 suppresses dermal mast cell activation and cutaneous inflammation"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Finally, pretreatment with SYM2081 significantly reduced skin inflammation in murine dermatitis and rosacea models."
    explanation: >-
      GEO summary reports rosacea-model validation of mast-cell-targeted
      suppression, relevant to the mast cell amplification step in this
      entry.
- accession: geo:GSE197981
  title: Innate type 2 immunity controls hair follicle commensalism by Demodex mites [2019]
  description: >-
    Mouse hair-follicle bulk RNA-seq from a study showing that ILC2-derived
    IL-13 restrains Demodex outgrowth; loss of this checkpoint drives
    inflammatory follicular programs and barrier loss. The study links its
    mouse findings to human rhinophymatous rosacea. Aligns with the Demodex
    Folliculorum Proliferation node.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 6
  conditions:
  - Demodex-colonized mouse hair follicles
  - ILC2/IL-13-deficient Demodex-colonized hair follicles
  publication: PMID:36044899
  evidence:
  - reference: GEO:GSE197981
    reference_title: "Innate type 2 immunity controls hair follicle commensalism by Demodex mites [2019]"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Humans with rhinophymatous acne rosacea, a nasal inflammatory condition associated with a high burden of Demodex, had increased HF inflammatory cells with decreased type 2 cytokines, consistent with the inverse relationship seen in mice."
    explanation: >-
      GEO summary ties the mouse Demodex-commensalism transcriptome to the
      high mite burden of human phymatous rosacea, supporting the Demodex
      proliferation mechanism in this entry.
  notes: >-
    Two small (n=4) sibling sub-series from the same study, GSE198657 and
    GSE197982, exist in GEO; only the primary series is recorded here.
- accession: dbgap:phs001672
  title: Million Veteran Program (MVP) rosacea genome-wide association summary statistics
  description: >-
    Genome-wide association summary statistics for rosacea (PheCode 695.3)
    from the VA Million Veteran Program phenome-wide atlas, the only public
    rosacea GWAS with deposited full summary statistics. European-ancestry
    analysis of 14,815 cases and 427,372 controls; access to individual
    level data is governed by dbGaP. The phenotype is an EHR PheCode, not a
    dermatologist-confirmed cohort.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: GWAS
  sample_count: 442187
  conditions:
  - rosacea (PheCode 695.3), European ancestry
  - rosacea (PheCode 695.3), African American or Afro-Caribbean ancestry
  - rosacea (PheCode 695.3), Hispanic or Latin American ancestry
  publication: PMID:39024449
  notes: >-
    No evidence block: the publication is a 2,068-trait atlas whose text
    does not name rosacea, so nothing in it can be quoted for this record.
    Trait-level results are catalogued by the GWAS Catalog, which has no
    reference prefix in this repository, so they are recorded here as
    provenance. GCST90476178 (European ancestry) lists eight genome-wide
    significant associations: rs6866614 (IRF1/CARINH), rs12203592 (IRF4),
    rs12898729 (HERC2), rs5743618 (TLR1), rs10806180 (near ELOVL4), and
    three signals given only as positions (chr2:28627629, chr7:50327367,
    chr16:90024970). The IRF4 and HERC2 hits replicate the 23andMe
    symptom-severity loci recorded in the genetic section, and the IRF1
    hit independently corroborates the Mendelian-randomization-derived IRF1
    entry. The TLR1 signal is mechanistically notable given the TLR2
    pathway in this entry, since TLR1 heterodimerizes with TLR2. The
    African-ancestry analysis (GCST90480451, 410 cases) reports nine
    associations dominated by pigmentation variants (rs16891982 SLC45A2,
    rs1805007 MC1R, rs12203592, rs12898729); with so few cases in an
    admixed sample these are more plausibly ancestry stratification than
    replication and are not curated as gene entries. The Hispanic-ancestry
    analysis (GCST90478792) reports no genome-wide significant hits.
- accession: arrayexpress:E-MTAB-16629
  title: Distinct diversity of skin cell populations of rhinophyma and hypertrophic scar illustrated by scRNA-seq
  description: >-
    10x Chromium single-cell RNA-seq of surgically resected rhinophyma
    (phymatous rosacea of the nose) compared with hypertrophic scar and
    healthy skin, designed to explain why rhinophyma tissue reverts toward
    normal after surgical debulking whereas hypertrophic scar recurs. The
    only single-cell dataset of end-stage phymatous disease; aligns with the
    sebaceous gland and soft tissue hyperplasia/fibrosis node.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 3
  conditions:
  - rhinophyma
  - hypertrophic scar
  - healthy skin
  notes: >-
    Released 2026-02-18 (BioStudies; 11 files). The repository lists three
    disease groups and no linked publication at time of curation; sample
    count is the repository's own figure. ArrayExpress records are resolved
    against the BioStudies API on each verifier run and are not cached, so
    this record carries no quoted evidence.
- accession: bioproject:PRJEB37562
  title: Skin microbiome characterization in rosacea patients and healthy controls
  description: >-
    Facial skin bacterial and fungal microbiome profiling in rosacea
    patients versus healthy controls. The project description reports
    subtype-specific shifts: increased Staphylococcus in
    erythematotelangiectatic and increased Streptococcus in papulopustular
    rosacea. The one cutaneous dysbiosis dataset stratified by clinical
    subtype.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_types:
  - preferred_term: skin of face
    term:
      id: UBERON:1000021
      label: skin of face
    tissue_term:
      preferred_term: skin of face
      term:
        id: UBERON:1000021
        label: skin of face
  conditions:
  - erythematotelangiectatic rosacea facial skin
  - papulopustular rosacea facial skin
  - healthy control facial skin
  notes: >-
    ENA holds this accession as a study record only: no run, sample or
    analysis objects are linked under it at time of curation, so the read
    data are not retrievable from the accession. The project registration
    (2020-06-26) and description match Woo et al. 2020, Br J Dermatol,
    PMID:32533846 ("Bacterial and fungal microbiome characterization in
    patients with rosacea and healthy controls"), but the repository lists
    no publication link, so the PMID is recorded here rather than in
    publication. No data_type is set because the schema enum has no value
    for amplicon (16S/ITS) metagenomics.
- accession: bioproject:PRJEB82826
  title: Multi-omics study of microbe-host interactions in rosacea
  description: >-
    Cutaneous microbiome (96 amplicon runs in ENA) with paired Demodex
    density and host skin transcriptome from rosacea patients before and
    after 30 days of topical 1% ivermectin, versus healthy volunteers. The
    dataset that separates the mite, microbiome and host-transcriptome arms
    of the Demodex mechanism: ivermectin cleared mites and normalized the
    host transcriptome without correcting bacterial dysbiosis.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MULTI_OMICS
  sample_types:
  - preferred_term: skin of face
    term:
      id: UBERON:1000021
      label: skin of face
    tissue_term:
      preferred_term: skin of face
      term:
        id: UBERON:1000021
        label: skin of face
  sample_count: 96
  conditions:
  - rosacea lesional skin, day 0 (pre-ivermectin)
  - rosacea lesional skin, day 30 (post-ivermectin)
  - healthy volunteer skin
  publication: PMID:40220854
  evidence:
  - reference: PMID:40220854
    reference_title: "Microbe-Host Interaction in Rosacea and Its Modulation through Topical Ivermectin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At day 0, distinct microbial community changes included the decrease in Cutibacterium acnes abundance, whereas Staphylococcus epidermidis colonization increased compared with that in healthy volunteers."
    explanation: >-
      The cutaneous dysbiosis signature measured in this dataset.
  - reference: PMID:40220854
    reference_title: "Microbe-Host Interaction in Rosacea and Its Modulation through Topical Ivermectin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, improvement of clinical signs during topical ivermectin is not associated with normalization of the bacterial microbiome but rather a decrease of transcriptomic dysregulation and mite density."
    explanation: >-
      Dissociates the treatment response from bacterial dysbiosis and ties
      it to mite clearance and host transcriptome normalization, the
      Demodex-directed reading of the acaricide link in this entry.
  notes: >-
    Sample count is the number of amplicon read runs in ENA; a sibling
    umbrella accession, PRJEB82848, carries the same title and description
    but no data objects and is not recorded separately. The host
    transcriptome arm is not among the ENA runs under this accession.
- accession: bioproject:PRJDB18292
  title: Topical ivermectin treatment of rosacea changes the bacterial microbiome of the skin
  description: >-
    16S bacterial microbiome of facial skin in rosacea patients sampled
    before and after topical ivermectin treatment (24 SRA experiments,
    DDBJ). A second, independent pre/post-ivermectin microbiome design
    complementing PRJEB82826.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_types:
  - preferred_term: skin of face
    term:
      id: UBERON:1000021
      label: skin of face
    tissue_term:
      preferred_term: skin of face
      term:
        id: UBERON:1000021
        label: skin of face
  sample_count: 24
  conditions:
  - rosacea facial skin, pre-ivermectin
  - rosacea facial skin, post-ivermectin
  publication: PMID:39481532
  notes: >-
    Publication is the same-titled 2025 J Invest Dermatol paper; its
    abstract could not be retrieved into the reference cache, so no quoted
    evidence is attached. No data_type is set because the schema enum has
    no value for amplicon (16S) metagenomics.
- accession: bioproject:PRJNA1189573
  title: Skin, blood, stool microbiome in rosacea
  description: >-
    16S rRNA bacterial microbiome profiled simultaneously in skin, blood
    and stool from rosacea patients and controls (93 SRA experiments): a
    multi-site design that directly tests the gut-skin axis rather than
    inferring it from cutaneous data alone.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_types:
  - preferred_term: skin of face
    term:
      id: UBERON:1000021
      label: skin of face
    tissue_term:
      preferred_term: skin of face
      term:
        id: UBERON:1000021
        label: skin of face
  - preferred_term: blood
    term:
      id: UBERON:0000178
      label: blood
    tissue_term:
      preferred_term: blood
      term:
        id: UBERON:0000178
        label: blood
  - preferred_term: feces
    term:
      id: UBERON:0001988
      label: feces
    tissue_term:
      preferred_term: feces
      term:
        id: UBERON:0001988
        label: feces
  sample_count: 93
  conditions:
  - rosacea patients (skin, blood, stool)
  - control participants (skin, blood, stool)
  notes: >-
    Sample count is the number of SRA experiments. No linked publication
    on the record at time of curation; no data_type is set because the
    schema enum has no value for amplicon (16S) metagenomics.
- accession: bioproject:PRJNA1288008
  title: Skin, blood, stool mycobiome in rosacea
  description: >-
    Fungal (ITS) mycobiome companion to PRJNA1189573, profiling skin, blood
    and stool from rosacea patients and controls (66 SRA experiments), so
    that fungal dysbiosis can be assessed alongside the bacterial data
    across the same body sites.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_types:
  - preferred_term: skin of face
    term:
      id: UBERON:1000021
      label: skin of face
    tissue_term:
      preferred_term: skin of face
      term:
        id: UBERON:1000021
        label: skin of face
  - preferred_term: blood
    term:
      id: UBERON:0000178
      label: blood
    tissue_term:
      preferred_term: blood
      term:
        id: UBERON:0000178
        label: blood
  - preferred_term: feces
    term:
      id: UBERON:0001988
      label: feces
    tissue_term:
      preferred_term: feces
      term:
        id: UBERON:0001988
        label: feces
  sample_count: 66
  conditions:
  - rosacea patients (skin, blood, stool)
  - control participants (skin, blood, stool)
  notes: >-
    Sample count is the number of SRA experiments. No linked publication
    on the record at time of curation; no data_type is set because the
    schema enum has no value for amplicon (ITS) metagenomics.
- accession: bioproject:PRJNA1191396
  title: Raw 16S rRNA Sequencing Data of Fecal Samples from Patients with Neurogenic Rosacea
  description: >-
    Fecal 16S rRNA microbiome from patients with neurogenic rosacea (34 SRA
    experiments), the burning/stinging-predominant presentation, probing
    the gut-skin-nerve axis behind the TRP and neuropeptide signaling node.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_types:
  - preferred_term: feces
    term:
      id: UBERON:0001988
      label: feces
    tissue_term:
      preferred_term: feces
      term:
        id: UBERON:0001988
        label: feces
  sample_count: 34
  conditions:
  - neurogenic rosacea fecal samples
  notes: >-
    Sample count is the number of SRA experiments. The record does not say
    whether controls are included. No linked publication on the record at
    time of curation; no data_type is set because the schema enum has no
    value for amplicon (16S) metagenomics.
differential_diagnoses:
- name: Acne
  disease_term:
    preferred_term: acne
    term:
      id: MONDO:0011438
      label: acne
  description: >-
    Acne can overlap clinically with papulopustular rosacea because both
    produce inflammatory papules and pustules on the face.
  distinguishing_features:
  - Acne more often shows open or closed comedones and broader sebaceous facial or truncal involvement.
  - Rosacea more often centers on persistent centrofacial erythema, flushing, and telangiectasia without comedones.
  evidence:
  - reference: PMID:11582639
    reference_title: "[Rosacea in the year 2001]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It can be difficult to distinguish acne vulgaris, seborrheic eczema, perioral dermatitis and lupus erythematosus from rosacea."
    explanation: >-
      This review explicitly lists acne vulgaris among the core differential
      diagnoses for rosacea.
- name: Seborrheic dermatitis
  disease_term:
    preferred_term: seborrheic dermatitis
    term:
      id: MONDO:0006608
      label: seborrheic dermatitis
  description: >-
    Facial seborrheic dermatitis can mimic rosacea when patients present with
    chronic erythema in sebaceous facial regions.
  distinguishing_features:
  - Seborrheic dermatitis more often has greasy yellow-white scale involving the eyebrows, nasolabial folds, and scalp.
  - Rosacea more often has flushing, telangiectasia, and papulopustular lesions without prominent greasy scale.
  evidence:
  - reference: PMID:11582639
    reference_title: "[Rosacea in the year 2001]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It can be difficult to distinguish acne vulgaris, seborrheic eczema, perioral dermatitis and lupus erythematosus from rosacea."
    explanation: >-
      This review explicitly identifies seborrheic eczema as a major
      rosacea mimic; the corresponding MONDO disease term used here is
      seborrheic dermatitis.
- name: Lupus erythematosus
  disease_term:
    preferred_term: lupus erythematosus
    term:
      id: MONDO:0004670
      label: lupus erythematosus
  description: >-
    Lupus erythematosus can resemble rosacea when facial erythema or a
    butterfly-pattern eruption predominates.
  distinguishing_features:
  - Lupus erythematosus more often has photosensitivity, scale, dyspigmentation, scarring plaques, or systemic autoimmune features.
  - Rosacea more often has trigger-provoked flushing, telangiectasia, and papulopustular centrofacial inflammation.
  evidence:
  - reference: PMID:11582639
    reference_title: "[Rosacea in the year 2001]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It can be difficult to distinguish acne vulgaris, seborrheic eczema, perioral dermatitis and lupus erythematosus from rosacea."
    explanation: >-
      This review explicitly lists lupus erythematosus among disorders that
      can be difficult to distinguish from rosacea.
  - reference: PMID:41695827
    reference_title: "Rosacea overlapping the malar rash: A diagnostic challenge in early systemic lupus erythematosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The coexistence of rosacea and lupus-like lesions delayed diagnosis, highlighting the need for clinicopathological correlation."
    explanation: >-
      This case report reinforces lupus erythematosus as a real-world
      rosacea mimic and overlap diagnosis.
- name: Systemic sclerosis
  disease_term:
    preferred_term: systemic sclerosis
    term:
      id: MONDO:0005100
      label: systemic sclerosis
  description: >-
    Rosacea-associated solid facial edema can mimic systemic sclerosis when
    facial induration or swelling dominates the presentation.
  distinguishing_features:
  - Systemic sclerosis more often has Raynaud phenomenon, acral involvement, and broader connective-tissue disease manifestations.
  - Morbihan-type rosacea edema may remain centered on the face with sparing of the hands and feet.
  evidence:
  - reference: PMID:41694889
    reference_title: "Facial Swelling in a Young Adult With Type 1 Diabetes: Morbihan Disease as a Scleroderma Mimic."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scleredema diabeticorum and Morbihan disease (solid facial edema) can mimic scleroderma, creating diagnostic challenges for rheumatologists."
    explanation: >-
      This directly supports systemic sclerosis-spectrum disease as a
      differential diagnosis for edematous rosacea presentations.
- name: Coccidioidomycosis
  disease_term:
    preferred_term: coccidioidomycosis
    term:
      id: MONDO:0005706
      label: coccidioidomycosis
  description: >-
    Cutaneous coccidioidomycosis can mimic rosacea-like dermatitis,
    particularly in immunocompromised patients living in endemic regions.
  distinguishing_features:
  - Coccidioidomycosis is favored by endemic exposure, immunosuppression, and biopsy evidence of fungal infection.
  - Rosacea lacks an infectious tissue diagnosis and more typically follows a chronic trigger-responsive vascular-inflammatory course.
  evidence:
  - reference: PMID:41017054
    reference_title: "Cutaneous Coccidioidomycosis Mimicking Rosacea in Immunosuppressed Patient, Arizona, USA, 2024."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An immunocompromised patient in Arizona, USA, experienced cutaneous coccidioidomycosis mimicking rosacea-like dermatitis"
    explanation: >-
      This directly documents cutaneous coccidioidomycosis as a rosacea
      mimic in the appropriate epidemiologic context.
- name: Lymphomatoid papulosis
  disease_term:
    preferred_term: lymphomatoid papulosis
    term:
      id: MONDO:0020326
      label: lymphomatoid papulosis
  description: >-
    Recurrent periocular nodules can be misclassified as papulopustular
    rosacea before biopsy reveals a CD30-positive lymphoproliferative lesion.
  distinguishing_features:
  - Lymphomatoid papulosis shows recurrent papulonodules with diagnostic CD30-positive atypical lymphoid infiltrates on histopathology.
  - Rosacea more typically produces diffuse erythema, papules, pustules, and telangiectasia rather than isolated recurrent nodules.
  evidence:
  - reference: PMID:40827152
    reference_title: "Recurrent Periocular Nodules: Lymphomatoid Papulosis in an Uncommon Anatomic Site."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "he was subsequently diagnosed with papulopustular rosacea and impetigo. However, despite multiple treatment trials, he still experienced recurrent flares with nodules"
    explanation: >-
      This case report documents an initial rosacea diagnosis later revised
      to lymphomatoid papulosis after biopsy.
discussions:
- discussion_id: gap_rosacea_innervated_vascularized_nam
  prompt: >-
    Can the neurovascular arm of rosacea (TRP-channel sensory activation,
    CGRP and substance P release, and the vasodilation behind flushing and
    burning) be modelled in a human non-animal system, given that every
    current NAM lacks sensory neurons and perfused microvessels?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#TRP and neuropeptide signaling
  - pathophysiology#Neurovascular vasodilation
  - experimental_models#
  rationale: >-
    The three NAMs in this entry cover the innate-immune and sebaceous arms:
    the papulopustular explant keeps the resident multicellular circuit,
    the SZ95 co-culture isolates the mite-sebocyte interface, and HaCaT
    keratinocytes reproduce TLR2 induction. None contains sensory neurons
    or a perfused vascular bed, so the flushing and burning phenotypes, and
    the fibroblast-derived vasodilatory signalling that single-cell
    profiling places upstream of them, can only be studied in the facial
    LL-37 mouse. Generic innervated and vascularized skin-on-chip platforms
    exist, but no rosacea-specific application has been published, so this
    is recorded as an absence of evidence rather than a mismatch between
    model and human.
  evidence:
  - reference: PMID:39384741
    reference_title: "Single-cell transcriptomics reveals aberrant skin-resident cell populations and identifies fibroblasts as a determinant in rosacea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most importantly, fibroblasts are identified as the leading cell type producing pro-inflammatory and vasodilative signals in rosacea."
    explanation: >-
      The vasodilatory program originates in a dermal cell type, so a model
      of it needs fibroblasts, vessels and nerves together, which no
      current rosacea NAM provides.
  - reference: PMID:36517318
    reference_title: "The temperature-sensitive receptors TRPV4 and TRPM8 have important roles in the pruritus of rosacea."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Increased expression of the temperature-sensitive receptors TRPV4 and TRPM8 was found in pruritic mouse skin and TG and human skin samples."
    explanation: >-
      The sensory-ganglion readout that makes the facial mouse model the
      only current system for this arm.
  proposed_experiments:
  - experiment_id: exp_rosacea_innervated_vascularized_skin_chip
    name: Innervated, vascularized skin-on-chip built from rosacea fibroblasts
    description: >-
      Reconstruct full-thickness skin on a perfusable microfluidic chip with
      a dermal microvessel network, patient-derived (or PTGDS-high
      pro-inflammatory) dermal fibroblasts, keratinocytes, mast cells and
      iPSC-derived TRPV1-positive sensory neurons; challenge with LL-37,
      heat and capsaicin; measure neuropeptide release, vessel dilation and
      permeability, and mast cell degranulation, with and without a CGRP
      receptor antagonist.
    perturbations:
    - name: LL-37 challenge
      target: pathophysiology#LL-37 generation
      description: >-
        Apply the processed cathelicidin peptide at lesional concentrations
        to the epidermal compartment.
    - name: Heat and capsaicin challenge
      target: pathophysiology#TRP and neuropeptide signaling
      description: >-
        Thermal ramp and capsaicin to activate TRPV1 on the innervating
        sensory neurons.
    readouts:
    - name: CGRP and substance P in the dermal effluent
      target: pathophysiology#TRP and neuropeptide signaling
      direction: INCREASED
      interpretation: >-
        Neuropeptide release from innervating sensory neurons on challenge.
    - name: Microvessel diameter and permeability
      target: pathophysiology#Neurovascular vasodilation
      direction: INCREASED
      interpretation: >-
        Live-imaged vasodilation and dextran leak, the tissue-level readout
        of flushing.
    controls:
    - name: Neuron-free chips
      description: >-
        Otherwise identical chips built without sensory neurons, to show
        which readouts require innervation.
    - name: Control-donor fibroblast arm
      description: >-
        Chips built with fibroblasts from healthy donors to test whether the
        rosacea fibroblast state is required for amplification.
    - name: Vehicle challenge
      description: >-
        Buffer-only challenge to establish the baseline vessel and
        neuropeptide response of the platform.
    would_support:
    - pathophysiology#TRP and neuropeptide signaling
    - pathophysiology#Neurovascular vasodilation
    would_refute:
    - pathophysiology#Neurovascular vasodilation
    supporting_outcome:
    - LL-37, heat or capsaicin evokes CGRP release and vessel dilation that a
      CGRP receptor antagonist blocks, and rosacea-derived fibroblasts amplify
      the response relative to control-donor fibroblasts.
    refuting_outcome:
    - Vessel dilation on challenge is unchanged by building the chip without
      sensory neurons or by CGRP receptor antagonism, placing the vasodilation
      outside the neuropeptide arm this experiment models.
    decision_criterion: >-
      A reproducible, antagonist-sensitive coupling from neuropeptide release
      to vessel dilation in at least three independent chip builds.
  notes: >-
    Posed after the 2026-09 NAM curation. Generic innervated skin-on-chip and
    vascularized skin-equivalent platforms are published outside rosacea; the
    gap is their application to this disease, not their existence.
references:
- reference: PMID:41918801
  title: "CO(2) Laser Resection of Giant Rhinophyma Under Local Anesthesia: A Case Report."
  findings: []
- reference: PMID:41695827
  title: "Rosacea overlapping the malar rash: A diagnostic challenge in early systemic lupus erythematosus."
  findings: []
- reference: PMID:41694889
  title: "Facial Swelling in a Young Adult With Type 1 Diabetes: Morbihan Disease as a Scleroderma Mimic."
  findings: []
- reference: PMID:41426892
  title: "Multimodal Management of Morbihan Disease: Isotretinoin, Intralesional Triamcinolone, and Ketotifen in a Recalcitrant Case."
  findings: []
- reference: PMID:41222206
  title: "Unilateral presentation of Morbihan's disease: a comprehensive case report and review."
  findings: []
- reference: PMID:41058755
  title: "Unilateral Peri-Orbital Oedema and Mechanical Ptosis: An Unusual Case Presentation of Rosacea."
  findings: []
- reference: PMID:41017054
  title: "Cutaneous Coccidioidomycosis Mimicking Rosacea in Immunosuppressed Patient, Arizona, USA, 2024."
  findings: []
- reference: PMID:40860281
  title: "Rhinophyma treated by skin graft: a case report."
  findings: []
- reference: PMID:40827152
  title: "Recurrent Periocular Nodules: Lymphomatoid Papulosis in an Uncommon Anatomic Site."
  findings: []
- reference: PMID:40791837
  title: "Rhinophyma Treatment with Blue Laser."
  findings: []
- reference: PMID:41909715
  title: "Distinct diversity of skin cell populations of rhinophyma and hypertrophic scar illustrated by scRNA-seq."
  findings: []
- reference: PMID:41800255
  title: "Targeting Macrophage-to-Myofibroblast Transition Mitigates Progression from Inflammation to Fibrosis in Rosacea."
  findings: []
- reference: PMID:41562711
  title: "Increased Expression of Angiopoietin 2 and Tie2 in Rosacea."
  findings: []
- reference: PMID:41203722
  title: "Lipidomic profiling of skin surface lipids in a cohort of Chinese patients with rosacea."
  findings: []
- reference: PMID:41139274
  title: "Integrated Multi-Omics and Experimental Validation Unveil the GZMK/NF-κB Axis Driving Inflammation and Fibroblast Proliferation in Rosacea: A Novel Drug Target Selection Strategy."
  findings: []
- reference: PMID:41087666
  title: "LAPTM5 exacerbates STING-mediated inflammation induced by LL-37 through stabilizing STING in rosacea."
  findings: []
- reference: PMID:40890957
  title: "Exploring Novel Biomarkers for Rosacea Through Cohort Study and Mendelian Randomisation."
  findings: []
- reference: PMID:40835085
  title: "Cathelicidin LL-37-Induced Transcriptome of Human Keratinocyte Identifies Chemokine CXCL10 Link to T-Cell-Mediated Rosacea Pathogenesis through Jak1/STAT1 Pathway."
  findings: []
- reference: PMID:40635520
  title: "Integrated Genomic and GEO Data Analysis Reveals Therapeutic Targets for Rosacea."
  findings: []
- reference: PMID:40567003
  title: "Novel Molecular Subtyping Revealed Molecular Pathways That Contribute to the Pathogenesis of Rosacea."
  findings: []
- reference: PMID:11582639
  title: "[Rosacea in the year 2001]."
  findings: []
- reference: PMID:27718519
  title: "Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel."
  findings: []
- reference: PMID:28150107
  title: "Acne and Rosacea."
  findings: []
- reference: PMID:34035646
  title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
  findings: []
- reference: PMID:35392024
  title: "Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea."
  findings: []
- reference: PMID:37626650
  title: "Exploring the Pathogenesis and Mechanism-Targeted Treatments of Rosacea: Previous Understanding and Updates."
  findings: []
- reference: PMID:39823143
  title: "Unveiling the Molecular Mechanisms of Rosacea: Insights From Transcriptomics and In Vitro Experiments."
  findings: []
- reference: PMID:40522449
  title: "[Ocular rosacea : Clinical aspects, diagnostics, management and treatment]."
  findings: []
- reference: PMID:25151931
  title: "[Physiopathology of rosacea]."
  findings: []
- reference: PMID:19428039
  title: "[Rhinophyma in a black African male patient]."
  findings: []

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