Benign Prostatic Hyperplasia

Complex MONDO:0010811 Show in embeddings browser Urological Disease

Age-related, dihydrotestosterone-dependent proliferation of prostatic stromal and glandular tissue in the transition zone, amplified by TGF-beta/ROCK signaling and local inflammation, enlarges the prostate. The enlarged gland compresses the prostatic urethra, combining a static mass effect with dynamic smooth muscle tone to produce bladder outlet obstruction. Chronic obstruction drives detrusor hypertrophy and later decompensation, yielding the lower urinary tract symptoms characteristic of the disease.

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9
Pathophys.
6
Phenotypes
5
Genes
9
Medical Actions
4
Datasets
8
References
2
Deep Research
⚙

Pathophysiology

9
Prostatic Stromal and Epithelial Proliferation
Age-related increase in prostatic stromal and glandular tissue, particularly in the transition zone. Dihydrotestosterone (DHT) drives proliferation through androgen receptors.
Prostatic Epithelial Cell CL:0002231 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Prostatic Epithelial Cell, annotated with epithelial cell of prostate (CL:0002231). CL:0002231 is a cell type from the Cell Ontology.
Cell Proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Cell Proliferation, annotated with cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:38654277 SUPPORT
"Proliferative nodular formation represents a characteristic pathological feature of benign prostatic hyperplasia (BPH) and serves as the primary cause for prostate volume enlargement and consequent lower urinary tract symptoms (LUTS)."
This evidence confirms that proliferative nodular formation in the transition zone is the primary pathological feature driving BPH symptoms.
Bladder Outlet Obstruction
Enlarged prostate compresses urethra, increasing resistance to urine flow. Static component from tissue mass and dynamic component from smooth muscle tone.
Detrusor Dysfunction
Chronic obstruction leads to detrusor muscle hypertrophy and later decompensation. Results in overactive bladder symptoms and incomplete emptying.
Smooth Muscle Cell CL:0000192 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Smooth Muscle Cell (CL:0000192). CL:0000192 is a cell type from the Cell Ontology.
Show evidence (1 reference)
PMID:37827216 SUPPORT
"Benign prostate hyperplasia (BPH) is caused by the nonmalignant enlargement of the transition zone of the prostate gland, leading to lower urinary tract symptoms."
This evidence supports that BPH-related enlargement causes lower urinary tract symptoms through bladder outlet obstruction and detrusor dysfunction.
Androgen-Dependent Growth
DHT converted from testosterone by 5-alpha reductase drives prostatic growth. 5-alpha reductase inhibitors shrink prostate.
Androgen Response GO:0030521 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Androgen Response, annotated with androgen receptor signaling pathway (GO:0030521). GO:0030521 is a biological process from the Gene Ontology.
Hypoxia-Induced Epithelial-Mesenchymal Transition
Hypoxic basal epithelial cells (BE5) drive nodular formation through upregulation of FOS and activation of EMT signaling, particularly in glandular nodules of the transition zone.
Epithelial to Mesenchymal Transition GO:0001837 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Epithelial to Mesenchymal Transition (GO:0001837). GO:0001837 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:38654277 SUPPORT
"A distinct subgroup of basal epithelial (BE) cells, referred to as BE5, was identified to play a crucial role in driving this progression through the hypoxia-induced epithelial-mesenchymal transition (EMT) signaling pathway."
This evidence identifies BE5 cells as key drivers of BPH through hypoxia-induced EMT, establishing a molecular mechanism for nodular formation.
TGF-beta/ROCK1 Mediated Stromal Hyperplasia
Aberrant activation of TGF-beta/ROCK1 pathway recruits mesenchymal stem cells that differentiate into fibroblasts and myofibroblasts, driving stromal hyperplasia and fibrosis.
TGF-beta Signaling GO:0007179 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves TGF-beta Signaling, annotated with transforming growth factor beta receptor signaling pathway (GO:0007179). GO:0007179 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:38711089 SUPPORT
"The aberrant activation of transforming growth factor β (TGF-β)/Rho kinase 1 (ROCK1) increased the stemness of BPH tissue by recruiting mesenchymal stem cells (MSCs), indicating the important role of embryonic reawakening in BPH."
This evidence demonstrates that TGF-beta/ROCK1 activation drives prostatic stromal hyperplasia through MSC recruitment and differentiation.
PMID:39455522 SUPPORT
"ROCK1 and ROCK2 were significantly up-regulated in BPH tissues, correlating with clinical parameters."
This evidence confirms upregulation of ROCK1/2 in human BPH tissues and their correlation with disease severity.
ROCK-Mediated Fibrosis and Beta-Catenin Signaling
ROCK1/2 activation promotes fibrosis, EMT, and cell proliferation by stabilizing beta-catenin and activating downstream targets including C-MYC, Snail, and Survivin. ROCK inhibition reverses these processes.
Wnt Signaling Pathway GO:0016055 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Wnt Signaling Pathway (GO:0016055). GO:0016055 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:39455522 SUPPORT
"ROCK downregulation inhibited the β-catenin signaling pathway (such as C-MYC, Snail and Survivin) and decreased β-catenin protein stability, while inhibiting TGF-β/Smad2/3 signaling."
This evidence shows ROCK signaling converges on beta-catenin pathway to drive BPH pathophysiology, providing a therapeutic target.
Oxidative Stress and Epithelial Plasticity
Low-androgen signaling epithelial populations show increased vulnerability to oxidative stress due to reduced antioxidant defenses. Mitochondrial ROS drives cell proliferation and stemness in BPH.
Response to Oxidative Stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Response to Oxidative Stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:37827216 SUPPORT
"Pb-PRL mouse prostates exhibited increased vulnerability to oxidative stress due to reduction of antioxidant enzyme expression. One-month treatment of Pb-PRL mice with anethole trithione (ATT), a specific inhibitor of mitochondrial ROS production, reduced prostate weight and voiding frequency."
This evidence demonstrates that oxidative stress contributes to BPH progression and that antioxidant therapy can reduce prostate enlargement and symptoms.
Inflammation and IL-6 Signaling
Periodontal pathogens and inflammatory stimuli upregulate IL-6, IL-6R, and gp130, activating the Akt pathway to promote epithelial and stromal proliferation while inhibiting apoptosis.
Inflammatory Response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Inflammatory Response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:38764065 SUPPORT
"P. gingivalis infection promoted prostate cell proliferation, inhibited apoptosis, and upregulated the expression of inflammatory cytokines interleukin-6 (IL-6; 4.47-fold), interleukin-6 receptor-α (IL-6Rα; 5.74-fold) and glycoprotein 130 (gp130; 4.47-fold) in prostatic tissue."
This evidence links oral-prostate inflammation to BPH progression through IL-6/IL-6R/gp130-mediated Akt signaling, representing a novel pathophysiological axis.
●

Phenotypes

6
Urinary Frequency VERY_FREQUENT Urological HP:0000012 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Urinary Frequency, annotated with Urinary urgency (HP:0000012). HP:0000012 is a phenotype from the Human Phenotype Ontology.
Nocturia VERY_FREQUENT Urological HP:0000017 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nocturia (HP:0000017). HP:0000017 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37827216 SUPPORT
"One-month treatment of Pb-PRL mice with anethole trithione (ATT), a specific inhibitor of mitochondrial ROS production, reduced prostate weight and voiding frequency."
This evidence shows that voiding frequency (including nocturia) is a key symptom of BPH that can be reduced through therapeutic intervention targeting oxidative stress.
Weak Urinary Stream VERY_FREQUENT Urological HP:0000016 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weak Stream, annotated with Urinary retention (HP:0000016). HP:0000016 is a phenotype from the Human Phenotype Ontology.
Hesitancy FREQUENT Urological HP:0000016 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Urinary Hesitancy, annotated with Urinary retention (HP:0000016). HP:0000016 is a phenotype from the Human Phenotype Ontology.
Difficulty initiating urination
Incomplete Emptying FREQUENT Urological HP:0000016 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Incomplete Emptying, annotated with Urinary retention (HP:0000016). HP:0000016 is a phenotype from the Human Phenotype Ontology.
Urinary Retention OCCASIONAL Urological HP:0000016 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Urinary Retention (HP:0000016). HP:0000016 is a phenotype from the Human Phenotype Ontology.
Acute retention is emergency
🧬

Genetic Associations

5
SRD5A2 (Risk Factor)
Gene: SRD5A2 hgnc:11285 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SRD5A2 (hgnc:11285). hgnc:11285 is a gene from the HUGO Gene Nomenclature Committee.
AR (Risk Factor)
Gene: AR hgnc:644 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is AR (hgnc:644). hgnc:644 is a gene from the HUGO Gene Nomenclature Committee.
ROCK1 (Causal)
Gene: ROCK1 hgnc:10251 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ROCK1 (hgnc:10251). hgnc:10251 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:39455522 SUPPORT
"ROCK1 and ROCK2 were significantly up-regulated in BPH tissues, correlating with clinical parameters."
This evidence establishes ROCK1 as causally implicated in BPH pathogenesis through upregulation and correlation with disease severity.
ROCK2 (Causal)
Gene: ROCK2 hgnc:10252 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ROCK2 (hgnc:10252). hgnc:10252 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:39455522 SUPPORT
"Y-27632 targeted the inhibition of ROCK1 & ROCK2 expression and inhibited cell proliferation, fibrosis, epithelial-mesenchymal transition (EMT), while induced cell apoptosis in a dose-dependent manner."
This evidence demonstrates ROCK2 as a causal factor in BPH through its role in proliferation, fibrosis, and EMT.
FOS (Causal)
Gene: FOS hgnc:3796 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FOS (hgnc:3796). hgnc:3796 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:38654277 SUPPORT
"A distinguishing characteristic of the BE5 cell subgroup in patients with BPH was its heightened hypoxia and upregulated expression of FOS."
This evidence identifies FOS upregulation as a key molecular driver of hypoxia-induced EMT in BPH nodular formation.
💊

Medical Actions

9
Alpha-Blockers
Action: alpha-blocker therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is alpha-blocker therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Relax prostatic smooth muscle (tamsulosin, alfuzosin, silodosin).
Show evidence (1 reference)
PMID:41271371 SUPPORT Other
"Alpha-blockers may be offered to patients with moderate to severe LUTS as first-line therapy."
The French LUTS Committee guidelines position alpha-blockers as first-line therapy for moderate to severe lower urinary tract symptoms related to benign prostatic hyperplasia.
5-Alpha Reductase Inhibitors
Action: 5-alpha reductase inhibitor therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is 5-alpha reductase inhibitor therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: finasteride CHEBI:5062 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses finasteride (CHEBI:5062). CHEBI:5062 is a therapeutic agent from Chemical Entities of Biological Interest.
Shrink prostate over months (finasteride, dutasteride).
Combination Therapy
Action: combination pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is combination pharmacotherapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Alpha-blocker plus 5-ARI for larger prostates.
PDE5 Inhibitors
Action: PDE5 inhibitor therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is PDE5 inhibitor therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Tadalafil approved for BPH and erectile dysfunction.
Show evidence (1 reference)
PMID:41271371 SUPPORT Other
"Tadalafil alone or combined with alpha-blockers is recommended for moderate to severe LUTS, particularly when erectile dysfunction coexists."
The French LUTS Committee guidelines recommend tadalafil, alone or with an alpha-blocker, for moderate to severe LUTS, particularly with coexisting erectile dysfunction.
TURP
Action: transurethral resection of the prostateNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is transurethral resection of the prostate, annotated with Transurethral Prostatic Resection (NCIT:C15343). NCIT:C15343 is a clinical intervention from the NCI Thesaurus. Ontology label: Transurethral Prostatic Resection NCIT:C15343
Transurethral resection, gold standard surgical treatment.
Laser Procedures
Action: laser prostate surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is laser prostate surgery, annotated with Laser Therapy (NCIT:C15466). NCIT:C15466 is a clinical intervention from the NCI Thesaurus. Ontology label: Laser Therapy NCIT:C15466
HoLEP, PVP for surgical candidates.
Minimally Invasive Therapies
Action: minimally invasive surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is minimally invasive surgery (NCIT:C172727). NCIT:C172727 is a clinical intervention from the NCI Thesaurus. Ontology label: Minimally Invasive Surgery NCIT:C172727
UroLift, Rezum for selected patients.
ROCK Inhibitors (Experimental)
Action: ROCK inhibitor therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is ROCK inhibitor therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Y-27632 and GSK269962A target ROCK1/2 to reduce fibrosis, EMT, and proliferation.
Show evidence (2 references)
PMID:39455522 SUPPORT
"At the in vivo level, Y-27632 reversed prostatic hyperplasia and fibrosis in BPH model rats to some extent."
This evidence demonstrates therapeutic potential of ROCK inhibition in reversing BPH pathology in animal models.
PMID:38711089 SUPPORT
"Inhibition of ROCK1 activation suppressed MSC migration and their potential for stromal differentiation."
This evidence shows ROCK1 inhibition (GSK269962A) prevents stromal hyperplasia by blocking MSC recruitment and differentiation.
Antioxidant Therapy (Experimental)
Action: antioxidant therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antioxidant therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: antioxidant NCIT:C275 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses antioxidant (NCIT:C275). NCIT:C275 is a therapeutic agent from the NCI Thesaurus.
Anethole trithione (ATT) inhibits mitochondrial ROS to reduce proliferation and stemness.
Show evidence (1 reference)
PMID:37827216 SUPPORT
"In human BPH-1 epithelial cells, ATT decreased mitochondrial metabolism, cell proliferation, and stemness features."
This evidence demonstrates antioxidant therapy can reduce key pathogenic features of BPH epithelial cells.
🌍

Environmental Factors

4
Age
Primary risk factor, rare before 40
Show evidence (1 reference)
PMID:34885733 SUPPORT Human Clinical
"The prevalence of this multifactorial disease increases with age."
States directly that BPH prevalence rises with age.
Obesity
Associated with larger prostate volume
Show evidence (1 reference)
PMID:21045705 SUPPORT Human Clinical
"Lifestyle and metabolic factors associated with significantly increased risks of benign prostatic hyperplasia and lower urinary tract symptoms include obesity, diabetes, and meat and fat consumption."
Names obesity among the lifestyle/metabolic factors with significantly increased BPH/LUTS risk.
Diabetes
Associated with BPH
Show evidence (1 reference)
PMID:21045705 SUPPORT Human Clinical
"Lifestyle and metabolic factors associated with significantly increased risks of benign prostatic hyperplasia and lower urinary tract symptoms include obesity, diabetes, and meat and fat consumption."
Names diabetes among the lifestyle/metabolic factors with significantly increased BPH/LUTS risk.
Physical Inactivity
Increases risk
Show evidence (1 reference)
PMID:21045705 SUPPORT Human Clinical
"Factors associated with decreased risks include physical activity, moderate alcohol intake, and vegetable consumption."
Physical activity is associated with decreased BPH/LUTS risk, so its absence (physical inactivity) is the corresponding risk factor.
🔬

Biochemical Markers

2
PSA (Variable)
Context: May be mildly elevated in BPH
Testosterone (Normal)
Context: Serum testosterone usually normal
📊

Related Datasets

4
A single cell transcriptional profile of benign prostatic hyperplasia geo:GSE290213
Benign prostatic hyperplasia (BPH) is characterized by excessive cell proliferation and inflammation and affects most aging men. The development of new therapies for BPH requires a deeper understanding of the underlying pathophysiology and cellular components of BPH. Single-cell RNA-sequencing was performed on prostate tissue from 15 patients undergoing holmium laser enucleation of the prostate for treatment of BPH. Clustering and differential expression analysis on aligned single cell RNA-seq data was performed to annotate all cell types. 16,234 cells were analyzed and specific stromal, epithelial, and immune subgroups were found to be strongly associated with inflammation.
human SINGLE CELL RNA SEQ n=27
PMID:41832222
Identified by GEO DataSets index search for Benign Prostatic Hyperplasia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Immune cell single-cell RNA sequencing analyses link an age-associated T cell subset to symptomatic benign prostatic hyperplasia geo:GSE295879
Benign prostatic hyperplasia (BPH) is among the most common age-associated diseases in men. Whether age-related changes in immune cells, termed immunosenescence, contribute to BPH is not clear. Specific T cell populations, in particular a subset of CD8+ T cells with high Granzyme K (GZMKhi) and low Granzyme B (GZMBlow) gene expression, have been associated with aging; however, the precise function and biological significance of these cells in age-related diseases is not known. The current study determine that Taa cells infiltrate aged human prostates and positively correlate with International Prostate Symptom Score (IPSS).
human SINGLE CELL RNA SEQ n=17
PMID:40692782
Identified by GEO DataSets index search for Benign Prostatic Hyperplasia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Genome-wide analysis of prostatic tissue gene expression from patients with benign prostatic hyperplasia geo:GSE101486
Analysis of gene expression in prostatic tissue from BPH patients with and without SRD5A2 gene methylation. The hypothesis is that BPH patients with DNA methylation of the SRD5A2 gene promoter have impaired conversion of testosterone to dihydrotestosterone, and therefore may use an alternative signaling pathway for prostatic tissue growth. Here, we compare gene expression profiles of SRD5A2-methylated vs. unmethylated prostatic tissue to nominate alternative biological pathways relevant in each molecular subtype of BPH.
human MICROARRAY n=22
PMID:28940538
Identified by GEO DataSets index search for Benign Prostatic Hyperplasia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Preclinical evaluation of waste-derived pomegranate extract (PWE) as potential preventing and therapeutic for benign prostatic hyperplasia massive:MSV000100818
This dataset contains LC-MS/MS proteomics data from liver and prostate tissues of Rattus norvegicus. Rats were treated with testosterone to model benign prostatic hyperplasia (BPH) and subsequently with pomegranate waste extract (PWE) to assess its effect on the tissue proteome.
Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Benign Prostatic Hyperplasia"). Retrieved 2026-08-02.
{ }

Source YAML

click to show 
name: Benign Prostatic Hyperplasia
creation_date: '2025-12-18T17:01:35Z'
description: >-
  Age-related, dihydrotestosterone-dependent proliferation of prostatic stromal and glandular tissue in the transition zone, amplified by TGF-beta/ROCK signaling and local inflammation, enlarges the prostate.
  The enlarged gland compresses the prostatic urethra, combining a static mass effect with dynamic smooth muscle tone to produce bladder outlet obstruction.
  Chronic obstruction drives detrusor hypertrophy and later decompensation, yielding the lower urinary tract symptoms characteristic of the disease.
category: Complex
parents:
- Urological Disease
disease_term:
  preferred_term: benign prostatic hyperplasia
  term:
    id: MONDO:0010811
    label: benign prostatic hyperplasia
pathophysiology:
- name: Prostatic Stromal and Epithelial Proliferation
  description: >
    Age-related increase in prostatic stromal and glandular tissue,
    particularly in the transition zone. Dihydrotestosterone (DHT)
    drives proliferation through androgen receptors.
  cell_types:
  - preferred_term: Prostatic Epithelial Cell
    term:
      id: CL:0002231
      label: epithelial cell of prostate
  biological_processes:
  - preferred_term: Cell Proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:38654277
    reference_title: "Integrating spatial transcriptomics and single-cell RNA-sequencing reveals the alterations in epithelial cells during nodular formation in benign prostatic hyperplasia."
    supports: SUPPORT
    snippet: "Proliferative nodular formation represents a characteristic pathological
      feature of benign prostatic hyperplasia (BPH) and serves as the primary cause
      for prostate volume enlargement and consequent lower urinary tract symptoms
      (LUTS)."
    explanation: This evidence confirms that proliferative nodular formation in
      the transition zone is the primary pathological feature driving BPH
      symptoms.
- name: Bladder Outlet Obstruction
  description: >
    Enlarged prostate compresses urethra, increasing resistance to
    urine flow. Static component from tissue mass and dynamic
    component from smooth muscle tone.
- name: Detrusor Dysfunction
  description: >
    Chronic obstruction leads to detrusor muscle hypertrophy and
    later decompensation. Results in overactive bladder symptoms
    and incomplete emptying.
  cell_types:
  - preferred_term: Smooth Muscle Cell
    term:
      id: CL:0000192
      label: smooth muscle cell
  evidence:
  - reference: PMID:37827216
    reference_title: "Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives Amplification of Androgen-Independent Epithelial Cell Populations Sensitive to Antioxidant Therapy."
    supports: SUPPORT
    snippet: "Benign prostate hyperplasia (BPH) is caused by the nonmalignant enlargement
      of the transition zone of the prostate gland, leading to lower urinary tract
      symptoms."
    explanation: This evidence supports that BPH-related enlargement causes
      lower urinary tract symptoms through bladder outlet obstruction and
      detrusor dysfunction.
- name: Androgen-Dependent Growth
  description: >
    DHT converted from testosterone by 5-alpha reductase drives
    prostatic growth. 5-alpha reductase inhibitors shrink prostate.
  biological_processes:
  - preferred_term: Androgen Response
    term:
      id: GO:0030521
      label: androgen receptor signaling pathway
- name: Hypoxia-Induced Epithelial-Mesenchymal Transition
  description: >
    Hypoxic basal epithelial cells (BE5) drive nodular formation through
    upregulation of FOS and activation of EMT signaling, particularly in
    glandular nodules of the transition zone.
  biological_processes:
  - preferred_term: Epithelial to Mesenchymal Transition
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
  evidence:
  - reference: PMID:38654277
    reference_title: "Integrating spatial transcriptomics and single-cell RNA-sequencing reveals the alterations in epithelial cells during nodular formation in benign prostatic hyperplasia."
    supports: SUPPORT
    snippet: "A distinct subgroup of basal epithelial (BE) cells, referred to as BE5,
      was identified to play a crucial role in driving this progression through the
      hypoxia-induced epithelial-mesenchymal transition (EMT) signaling pathway."
    explanation: This evidence identifies BE5 cells as key drivers of BPH
      through hypoxia-induced EMT, establishing a molecular mechanism for
      nodular formation.
- name: TGF-beta/ROCK1 Mediated Stromal Hyperplasia
  description: >
    Aberrant activation of TGF-beta/ROCK1 pathway recruits mesenchymal
    stem cells that differentiate into fibroblasts and myofibroblasts,
    driving stromal hyperplasia and fibrosis.
  biological_processes:
  - preferred_term: TGF-beta Signaling
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
  evidence:
  - reference: PMID:38711089
    reference_title: "Aberrant activation of TGF-β/ROCK1 enhances stemness during prostatic stromal hyperplasia."
    supports: SUPPORT
    snippet: "The aberrant activation of transforming growth factor β (TGF-β)/Rho
      kinase 1 (ROCK1) increased the stemness of BPH tissue by recruiting mesenchymal
      stem cells (MSCs), indicating the important role of embryonic reawakening in
      BPH."
    explanation: This evidence demonstrates that TGF-beta/ROCK1 activation
      drives prostatic stromal hyperplasia through MSC recruitment and
      differentiation.
  - reference: PMID:39455522
    reference_title: "Y-27632 targeting ROCK1&2 modulates cell growth, fibrosis and epithelial-mesenchymal transition in hyperplastic prostate by inhibiting β-catenin pathway."
    supports: SUPPORT
    snippet: "ROCK1 and ROCK2 were significantly up-regulated in BPH tissues, correlating
      with clinical parameters."
    explanation: This evidence confirms upregulation of ROCK1/2 in human BPH
      tissues and their correlation with disease severity.
- name: ROCK-Mediated Fibrosis and Beta-Catenin Signaling
  description: >
    ROCK1/2 activation promotes fibrosis, EMT, and cell proliferation by
    stabilizing beta-catenin and activating downstream targets including
    C-MYC, Snail, and Survivin. ROCK inhibition reverses these processes.
  biological_processes:
  - preferred_term: Wnt Signaling Pathway
    term:
      id: GO:0016055
      label: Wnt signaling pathway
  evidence:
  - reference: PMID:39455522
    reference_title: "Y-27632 targeting ROCK1&2 modulates cell growth, fibrosis and epithelial-mesenchymal transition in hyperplastic prostate by inhibiting β-catenin pathway."
    supports: SUPPORT
    snippet: "ROCK downregulation inhibited the β-catenin signaling pathway (such
      as C-MYC, Snail and Survivin) and decreased β-catenin protein stability, while
      inhibiting TGF-β/Smad2/3 signaling."
    explanation: This evidence shows ROCK signaling converges on beta-catenin
      pathway to drive BPH pathophysiology, providing a therapeutic target.
- name: Oxidative Stress and Epithelial Plasticity
  description: >
    Low-androgen signaling epithelial populations show increased vulnerability
    to oxidative stress due to reduced antioxidant defenses. Mitochondrial
    ROS drives cell proliferation and stemness in BPH.
  biological_processes:
  - preferred_term: Response to Oxidative Stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  evidence:
  - reference: PMID:37827216
    reference_title: "Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives Amplification of Androgen-Independent Epithelial Cell Populations Sensitive to Antioxidant Therapy."
    supports: SUPPORT
    snippet: "Pb-PRL mouse prostates exhibited increased vulnerability to oxidative
      stress due to reduction of antioxidant enzyme expression. One-month treatment
      of Pb-PRL mice with anethole trithione (ATT), a specific inhibitor of mitochondrial
      ROS production, reduced prostate weight and voiding frequency."
    explanation: This evidence demonstrates that oxidative stress contributes to
      BPH progression and that antioxidant therapy can reduce prostate
      enlargement and symptoms.
- name: Inflammation and IL-6 Signaling
  description: >
    Periodontal pathogens and inflammatory stimuli upregulate IL-6, IL-6R,
    and gp130, activating the Akt pathway to promote epithelial and stromal
    proliferation while inhibiting apoptosis.
  biological_processes:
  - preferred_term: Inflammatory Response
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:38764065
    reference_title: "P. gingivalis in oral-prostate axis exacerbates benign prostatic hyperplasia via IL-6/IL-6R pathway."
    supports: SUPPORT
    snippet: "P. gingivalis infection promoted prostate cell proliferation, inhibited
      apoptosis, and upregulated the expression of inflammatory cytokines interleukin-6
      (IL-6; 4.47-fold), interleukin-6 receptor-α (IL-6Rα; 5.74-fold) and glycoprotein
      130 (gp130; 4.47-fold) in prostatic tissue."
    explanation: This evidence links oral-prostate inflammation to BPH
      progression through IL-6/IL-6R/gp130-mediated Akt signaling, representing
      a novel pathophysiological axis.
phenotypes:
- name: Urinary Frequency
  category: Urological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Urinary Frequency
    term:
      id: HP:0000012
      label: Urinary urgency
- name: Nocturia
  category: Urological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Nocturia
    term:
      id: HP:0000017
      label: Nocturia
  evidence:
  - reference: PMID:37827216
    reference_title: "Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives Amplification of Androgen-Independent Epithelial Cell Populations Sensitive to Antioxidant Therapy."
    supports: SUPPORT
    snippet: "One-month treatment of Pb-PRL mice with anethole trithione (ATT), a
      specific inhibitor of mitochondrial ROS production, reduced prostate weight
      and voiding frequency."
    explanation: This evidence shows that voiding frequency (including nocturia)
      is a key symptom of BPH that can be reduced through therapeutic
      intervention targeting oxidative stress.
- name: Weak Urinary Stream
  category: Urological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Weak Stream
    term:
      id: HP:0000016
      label: Urinary retention
- name: Hesitancy
  category: Urological
  frequency: FREQUENT
  notes: Difficulty initiating urination
  phenotype_term:
    preferred_term: Urinary Hesitancy
    term:
      id: HP:0000016
      label: Urinary retention
- name: Incomplete Emptying
  category: Urological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Incomplete Emptying
    term:
      id: HP:0000016
      label: Urinary retention
- name: Urinary Retention
  category: Urological
  frequency: OCCASIONAL
  notes: Acute retention is emergency
  phenotype_term:
    preferred_term: Urinary Retention
    term:
      id: HP:0000016
      label: Urinary retention
biochemical:
- name: PSA
  presence: Variable
  context: May be mildly elevated in BPH
- name: Testosterone
  presence: Normal
  context: Serum testosterone usually normal
genetic:
- name: SRD5A2
  gene_term:
    preferred_term: SRD5A2
    term:
      id: hgnc:11285
      label: SRD5A2
  association: Risk Factor
  notes: 5-alpha reductase
- name: AR
  gene_term:
    preferred_term: AR
    term:
      id: hgnc:644
      label: AR
  association: Risk Factor
  notes: Androgen receptor CAG repeats
- name: ROCK1
  gene_term:
    preferred_term: ROCK1
    term:
      id: hgnc:10251
      label: ROCK1
  association: Causal
  notes: Rho-associated kinase 1, upregulated in BPH, drives fibrosis and EMT
  evidence:
  - reference: PMID:39455522
    reference_title: "Y-27632 targeting ROCK1&2 modulates cell growth, fibrosis and epithelial-mesenchymal transition in hyperplastic prostate by inhibiting β-catenin pathway."
    supports: SUPPORT
    snippet: "ROCK1 and ROCK2 were significantly up-regulated in BPH tissues, correlating
      with clinical parameters."
    explanation: This evidence establishes ROCK1 as causally implicated in BPH
      pathogenesis through upregulation and correlation with disease severity.
- name: ROCK2
  gene_term:
    preferred_term: ROCK2
    term:
      id: hgnc:10252
      label: ROCK2
  association: Causal
  notes: Rho-associated kinase 2, upregulated in BPH, promotes proliferation and
    fibrosis
  evidence:
  - reference: PMID:39455522
    reference_title: "Y-27632 targeting ROCK1&2 modulates cell growth, fibrosis and epithelial-mesenchymal transition in hyperplastic prostate by inhibiting β-catenin pathway."
    supports: SUPPORT
    snippet: "Y-27632 targeted the inhibition of ROCK1 & ROCK2 expression and inhibited
      cell proliferation, fibrosis, epithelial-mesenchymal transition (EMT), while
      induced cell apoptosis in a dose-dependent manner."
    explanation: This evidence demonstrates ROCK2 as a causal factor in BPH
      through its role in proliferation, fibrosis, and EMT.
- name: FOS
  gene_term:
    preferred_term: FOS
    term:
      id: hgnc:3796
      label: FOS
  association: Causal
  notes: c-Fos transcription factor, upregulated in hypoxic BE5 cells, drives
    EMT
  evidence:
  - reference: PMID:38654277
    reference_title: "Integrating spatial transcriptomics and single-cell RNA-sequencing reveals the alterations in epithelial cells during nodular formation in benign prostatic hyperplasia."
    supports: SUPPORT
    snippet: "A distinguishing characteristic of the BE5 cell subgroup in patients
      with BPH was its heightened hypoxia and upregulated expression of FOS."
    explanation: This evidence identifies FOS upregulation as a key molecular
      driver of hypoxia-induced EMT in BPH nodular formation.
environmental:
- name: Age
  notes: Primary risk factor, rare before 40
  evidence:
  - reference: PMID:34885733
    reference_title: "Treatment of Benign Prostatic Hyperplasia by Natural Drugs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of this multifactorial disease increases with age."
    explanation: States directly that BPH prevalence rises with age.
- name: Obesity
  notes: Associated with larger prostate volume
  evidence:
  - reference: PMID:21045705
    reference_title: "Lifestyle factors, benign prostatic hyperplasia, and lower urinary tract symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lifestyle and metabolic factors associated with significantly increased risks of benign prostatic hyperplasia and lower urinary tract symptoms include obesity, diabetes, and meat and fat consumption."
    explanation: Names obesity among the lifestyle/metabolic factors with significantly increased BPH/LUTS risk.
- name: Diabetes
  notes: Associated with BPH
  evidence:
  - reference: PMID:21045705
    reference_title: "Lifestyle factors, benign prostatic hyperplasia, and lower urinary tract symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lifestyle and metabolic factors associated with significantly increased risks of benign prostatic hyperplasia and lower urinary tract symptoms include obesity, diabetes, and meat and fat consumption."
    explanation: Names diabetes among the lifestyle/metabolic factors with significantly increased BPH/LUTS risk.
- name: Physical Inactivity
  notes: Increases risk
  evidence:
  - reference: PMID:21045705
    reference_title: "Lifestyle factors, benign prostatic hyperplasia, and lower urinary tract symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Factors associated with decreased risks include physical activity, moderate alcohol intake, and vegetable consumption."
    explanation: Physical activity is associated with decreased BPH/LUTS risk, so its absence (physical inactivity) is the corresponding risk factor.
treatments:
- name: Alpha-Blockers
  description: Relax prostatic smooth muscle (tamsulosin, alfuzosin, silodosin).
  treatment_term:
    preferred_term: alpha-blocker therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:41271371
    reference_title: "Non-interventional and medical management of lower urinary tract symptoms related to benign prostatic hyperplasia in men: Guidelines of the French LUTS Committee (CTMH)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Alpha-blockers may be offered to patients with moderate to severe LUTS as first-line therapy."
    explanation: The French LUTS Committee guidelines position alpha-blockers as first-line therapy for moderate to severe lower urinary tract symptoms related to benign prostatic hyperplasia.
- name: 5-Alpha Reductase Inhibitors
  description: Shrink prostate over months (finasteride, dutasteride).
  treatment_term:
    preferred_term: 5-alpha reductase inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: finasteride
      term:
        id: CHEBI:5062
        label: finasteride
- name: Combination Therapy
  description: Alpha-blocker plus 5-ARI for larger prostates.
  treatment_term:
    preferred_term: combination pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: PDE5 Inhibitors
  description: Tadalafil approved for BPH and erectile dysfunction.
  treatment_term:
    preferred_term: PDE5 inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:41271371
    reference_title: "Non-interventional and medical management of lower urinary tract symptoms related to benign prostatic hyperplasia in men: Guidelines of the French LUTS Committee (CTMH)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Tadalafil alone or combined with alpha-blockers is recommended for moderate to severe LUTS, particularly when erectile dysfunction coexists."
    explanation: The French LUTS Committee guidelines recommend tadalafil, alone or with an alpha-blocker, for moderate to severe LUTS, particularly with coexisting erectile dysfunction.
- name: TURP
  description: Transurethral resection, gold standard surgical treatment.
  treatment_term:
    preferred_term: transurethral resection of the prostate
    term:
      id: NCIT:C15343
      label: Transurethral Prostatic Resection
- name: Laser Procedures
  description: HoLEP, PVP for surgical candidates.
  treatment_term:
    preferred_term: laser prostate surgery
    term:
      id: NCIT:C15466
      label: Laser Therapy
- name: Minimally Invasive Therapies
  description: UroLift, Rezum for selected patients.
  treatment_term:
    preferred_term: minimally invasive surgery
    term:
      id: NCIT:C172727
      label: Minimally Invasive Surgery
- name: ROCK Inhibitors (Experimental)
  description: Y-27632 and GSK269962A target ROCK1/2 to reduce fibrosis, EMT,
    and proliferation.
  treatment_term:
    preferred_term: ROCK inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:39455522
    reference_title: "Y-27632 targeting ROCK1&2 modulates cell growth, fibrosis and epithelial-mesenchymal transition in hyperplastic prostate by inhibiting β-catenin pathway."
    supports: SUPPORT
    snippet: "At the in vivo level, Y-27632 reversed prostatic hyperplasia and fibrosis
      in BPH model rats to some extent."
    explanation: This evidence demonstrates therapeutic potential of ROCK
      inhibition in reversing BPH pathology in animal models.
  - reference: PMID:38711089
    reference_title: "Aberrant activation of TGF-β/ROCK1 enhances stemness during prostatic stromal hyperplasia."
    supports: SUPPORT
    snippet: "Inhibition of ROCK1 activation suppressed MSC migration and their potential
      for stromal differentiation."
    explanation: This evidence shows ROCK1 inhibition (GSK269962A) prevents
      stromal hyperplasia by blocking MSC recruitment and differentiation.
- name: Antioxidant Therapy (Experimental)
  description: Anethole trithione (ATT) inhibits mitochondrial ROS to reduce
    proliferation and stemness.
  treatment_term:
    preferred_term: antioxidant therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antioxidant
      term:
        id: NCIT:C275
        label: Antioxidant
  evidence:
  - reference: PMID:37827216
    reference_title: "Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives Amplification of Androgen-Independent Epithelial Cell Populations Sensitive to Antioxidant Therapy."
    supports: SUPPORT
    snippet: "In human BPH-1 epithelial cells, ATT decreased mitochondrial metabolism,
      cell proliferation, and stemness features."
    explanation: This evidence demonstrates antioxidant therapy can reduce key
      pathogenic features of BPH epithelial cells.
datasets:
- accession: geo:GSE290213
  title: A single cell transcriptional profile of benign prostatic hyperplasia
  description: Benign prostatic hyperplasia (BPH) is characterized by excessive cell proliferation and inflammation and affects most aging men. The development of new therapies for BPH requires a deeper understanding of the underlying pathophysiology and cellular components of BPH. Single-cell RNA-sequencing was performed on prostate tissue from 15 patients undergoing holmium laser enucleation of the prostate for treatment of BPH. Clustering and differential expression analysis on aligned single cell RNA-seq data was performed to annotate all cell types. 16,234 cells were analyzed and specific stromal, epithelial, and immune subgroups were found to be strongly associated with inflammation.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 27
  publication: PMID:41832222
  notes: Identified by GEO DataSets index search for Benign Prostatic Hyperplasia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE295879
  title: Immune cell single-cell RNA sequencing analyses link an age-associated T cell subset to symptomatic benign prostatic hyperplasia
  description: Benign prostatic hyperplasia (BPH) is among the most common age-associated diseases in men. Whether age-related changes in immune cells, termed immunosenescence, contribute to BPH is not clear. Specific T cell populations, in particular a subset of CD8+ T cells with high Granzyme K (GZMKhi) and low Granzyme B (GZMBlow) gene expression, have been associated with aging; however, the precise function and biological significance of these cells in age-related diseases is not known. The current study determine that Taa cells infiltrate aged human prostates and positively correlate with International Prostate Symptom Score (IPSS).
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 17
  publication: PMID:40692782
  notes: Identified by GEO DataSets index search for Benign Prostatic Hyperplasia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE101486
  title: Genome-wide analysis of prostatic tissue gene expression from patients with benign prostatic hyperplasia
  description: Analysis of gene expression in prostatic tissue from BPH patients with and without SRD5A2 gene methylation. The hypothesis is that BPH patients with DNA methylation of the SRD5A2 gene promoter have impaired conversion of testosterone to dihydrotestosterone, and therefore may use an alternative signaling pathway for prostatic tissue growth. Here, we compare gene expression profiles of SRD5A2-methylated vs. unmethylated prostatic tissue to nominate alternative biological pathways relevant in each molecular subtype of BPH.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 22
  publication: PMID:28940538
  notes: Identified by GEO DataSets index search for Benign Prostatic Hyperplasia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: massive:MSV000100818
  title: Preclinical evaluation of waste-derived pomegranate extract (PWE) as potential preventing and therapeutic for benign prostatic hyperplasia
  description: This dataset contains LC-MS/MS proteomics data from liver and prostate tissues of Rattus norvegicus. Rats were treated with testosterone to model benign prostatic hyperplasia (BPH) and subsequently with pomegranate waste extract (PWE) to assess its effect on the tissue proteome.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Benign Prostatic Hyperplasia"). Retrieved 2026-08-02.
references:
- reference: DOI:10.1016/j.ajpath.2023.09.010
  title: Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives
    Amplification of Androgen-Independent Epithelial Cell Populations Sensitive
    to Antioxidant Therapy
  findings: []
- reference: DOI:10.1101/2025.08.12.669857
  title: Immune dysregulation in the prostates of C57BL/6 <sup>Aire-/-</sup>
    mice mirrors that seen in human benign prostatic hyperplasia
  findings: []
- reference: DOI:10.1172/jci.insight.176479
  title: Spatial transcriptomics identifies candidate stromal drivers of benign
    prostatic hyperplasia
  findings: []
- reference: DOI:10.1186/s12964-024-01644-4
  title: Aberrant activation of TGF-β/ROCK1 enhances stemness during prostatic
    stromal hyperplasia
  findings: []
- reference: DOI:10.1186/s12967-024-05212-9
  title: Integrating spatial transcriptomics and single-cell RNA-sequencing
    reveals the alterations in epithelial cells during nodular formation in
    benign prostatic hyperplasia
  findings: []
- reference: DOI:10.1186/s13062-024-00504-y
  title: Phosphodiesterase type 5 inhibitor tadalafil reduces prostatic fibrosis
    via MiR-3126-3p/FGF9 axis in benign prostatic hyperplasia
  findings: []
- reference: DOI:10.1186/s40779-024-00533-8
  title: P. gingivalis in oral-prostate axis exacerbates benign prostatic
    hyperplasia via IL-6/IL-6R pathway
  findings: []
- reference: DOI:10.1186/s43556-024-00216-9
  title: Y-27632 targeting ROCK1&amp;2 modulates cell growth, fibrosis and
    epithelial-mesenchymal transition in hyperplastic prostate by inhibiting
    β-catenin pathway
  findings: []
📚

References & Deep Research

References

8
DOI:10.1016/j.ajpath.2023.09.010
Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives Amplification of Androgen-Independent Epithelial Cell Populations Sensitive to Antioxidant Therapy
No top-level findings curated for this source.
DOI:10.1101/2025.08.12.669857
Immune dysregulation in the prostates of C57BL/6 <sup>Aire-/-</sup> mice mirrors that seen in human benign prostatic hyperplasia
No top-level findings curated for this source.
DOI:10.1172/jci.insight.176479
Spatial transcriptomics identifies candidate stromal drivers of benign prostatic hyperplasia
No top-level findings curated for this source.
DOI:10.1186/s12964-024-01644-4
Aberrant activation of TGF-β/ROCK1 enhances stemness during prostatic stromal hyperplasia
No top-level findings curated for this source.
DOI:10.1186/s12967-024-05212-9
Integrating spatial transcriptomics and single-cell RNA-sequencing reveals the alterations in epithelial cells during nodular formation in benign prostatic hyperplasia
No top-level findings curated for this source.
DOI:10.1186/s13062-024-00504-y
Phosphodiesterase type 5 inhibitor tadalafil reduces prostatic fibrosis via MiR-3126-3p/FGF9 axis in benign prostatic hyperplasia
No top-level findings curated for this source.
DOI:10.1186/s40779-024-00533-8
P. gingivalis in oral-prostate axis exacerbates benign prostatic hyperplasia via IL-6/IL-6R pathway
No top-level findings curated for this source.
DOI:10.1186/s43556-024-00216-9
Y-27632 targeting ROCK1&amp;2 modulates cell growth, fibrosis and epithelial-mesenchymal transition in hyperplastic prostate by inhibiting β-catenin pathway
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Benign Prostatic Hyperplasia
  • Category: Complex
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 23

Key Pathophysiology Nodes

  • Prostatic Stromal and Epithelial Proliferation
  • Bladder Outlet Obstruction
  • Detrusor Dysfunction
  • Androgen-Dependent Growth
  • Hypoxia-Induced Epithelial-Mesenchymal Transition
  • TGF-beta/ROCK1 Mediated Stromal Hyperplasia
  • ROCK-Mediated Fibrosis and Beta-Catenin Signaling
  • Oxidative Stress and Epithelial Plasticity
  • Inflammation and IL-6 Signaling
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1016/j.ajpath.2023.09.010
  • DOI:10.1101/2025.08.12.669857
  • DOI:10.1172/jci.insight.176479
  • DOI:10.1186/s12964-024-01644-4
  • DOI:10.1186/s12967-024-05212-9
  • DOI:10.1186/s13062-024-00504-y
  • DOI:10.1186/s40779-024-00533-8
  • DOI:10.1186/s43556-024-00216-9
Falcon ▸
Pathophysiology description (narrative)
Edison Scientific Literature 17 citations 2025-12-18T00:07:39.848752

Pathophysiology description (narrative) BPH is characterized by nodular proliferation localized to the prostate transition zone (TZ), driven by a coordinated set of epithelial and stromal programs that reactivate developmental (embryonic) signals and are sustained by inflammation, fibrosis, and metabolic stress. Spatial transcriptomics coupled with scRNA-seq resolve an initiating basal epithelial subgroup (BE5) with a hypoxia signature and c-Fos (FOS) upregulation, which positions BE5 as both the initiating cell of nodular formation and as a transitional state in luminal-to-basal reprogramming; hypoxia-induced EMT and proliferation are especially enriched in glandular nodules (vs stromal nodules) (mechanistic link: hypoxia→FOS→EMT) (fei2024integratingspatialtranscriptomics pages 15-15, fei2024integratingspatialtranscriptomics pages 1-2). In parallel, stroma adjacent to hyperplastic ducts expresses inductive factors—including IGF1 and CXCL13—co-localized in fibroblasts with IGF1R and CXCR5 expressed on adjacent epithelium; IGF1 is necessary for BPH organoid/spheroid growth, substantiating a stromal→epithelial induction axis (fei2024integratingspatialtranscriptomics pages 15-15). Fibrosis and ECM remodeling are reinforced by aberrant TGF-β/ROCK activation: TGF-β/ROCK1 recruits LepR+ mesenchymal stem cells (MSCs) that differentiate into fibroblasts/myofibroblasts and amplify stromal hyperplasia; pharmacologic ROCK1 inhibition (GSK269962A) suppresses MSC migration/differentiation in vivo (li2024aberrantactivationof pages 1-3). ROCK1/2 also crosstalk with WNT/β-catenin and TGF-β signaling to promote epithelial proliferation, EMT, and collagen deposition; nonselective ROCK inhibition (Y‑27632) decreases β‑catenin stability and downstream effectors (MYC, SNAI1) and reduces hyperplasia and fibrosis in a testosterone-induced rat model (shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11). Oxidative stress and epithelial plasticity are integral: in a BPH mouse model, low-androgen signaling epithelial populations analogous to club-like cells expand and display reduced antioxidant defenses; mitochondrial ROS inhibition (anethole trithione) reduces prostate weight and voiding frequency and suppresses epithelial proliferation and stemness in vitro and ex vivo (santos2024cellplasticityin pages 1-2). Clinical symptoms (LUTS) result from mechanical obstruction in the TZ and increased smooth muscle tone; mechanistically, microbial and inflammatory stimuli can aggravate epithelial proliferation and fibrosis via IL‑6/IL‑6R/gp130→AKT signaling (periodontal P. gingivalis model), linking systemic/oral inflammation to prostatic hyperplasia (fei2024integratingspatialtranscriptomics pages 15-15).

Key concepts and definitions - Nodular hyperplasia (TZ): multicellular units of proliferating epithelium and stroma in the transition zone, the anatomical basis of LUTS (fei2024integratingspatialtranscriptomics pages 15-15). - Stromal–epithelial induction: fibroblast-derived secreted factors (IGF1, CXCL13) activating epithelial RTKs and chemokine receptors to drive ductal proliferation (fei2024integratingspatialtranscriptomics pages 15-15). - Fibrosis/myofibroblast activation: TGF‑β/ROCK1-dependent recruitment/differentiation of MSCs and activation of ECM programs (li2024aberrantactivationof pages 1-3). - Epithelial plasticity/EMT: hypoxia/FOS- and TGF‑β/ROCK‑driven EMT and luminal-to-basal transitions, enriching club-like and basal progenitors in nodules (fei2024integratingspatialtranscriptomics pages 15-15, santos2024cellplasticityin pages 1-2). - Oxidative stress: mitochondrial ROS promotes proliferation and stemness; antioxidant therapy mitigates organ-level and cellular phenotypes (santos2024cellplasticityin pages 1-2). - Inflammatory signaling: IL‑6/IL‑6R/gp130→AKT activation by microbial LPS accelerates proliferation and fibrosis; immune infiltrates reinforce stromal activation (fei2024integratingspatialtranscriptomics pages 15-15).

Recent developments and latest research (2023–2024) - Spatial/scRNA: Identification of BE5 hypoxic basal subgroup as nodular initiator and transitional state (LE→BE) with FOS-driven EMT in BPH; stronger EMT/proliferation in glandular vs stromal nodules (Fei 2024; J Transl Med; Apr 2024; https://doi.org/10.1186/s12967-024-05212-9) (fei2024integratingspatialtranscriptomics pages 15-15, fei2024integratingspatialtranscriptomics pages 1-2). - Stromal drivers: IGF1 and CXCL13 coexpressed by BPH fibroblasts, with IGF1R/CXCR5 on adjacent epithelium; IGF1 is necessary for BPH spheroids and organoids, supporting a reawakened embryonic stromal induction program (Pollack 2024; JCI Insight; Jan 2024; https://doi.org/10.1172/jci.insight.176479) (fei2024integratingspatialtranscriptomics pages 15-15). - ROCK/TGF-β cross-talk: Upregulated ROCK1/2 in human BPH and testosterone-BPH rats, with ROCK inhibition lowering β‑catenin and TGF‑β/Smad activation, reducing EMT/fibrosis and proliferation; in vivo, Y‑27632 decreased prostate index and collagen (Shan 2024; Mol Biomed; Oct 2024; https://doi.org/10.1186/s43556-024-00216-9) (shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11). - MSC recruitment/stemness: TGF‑β/ROCK1 recruits LepR+ MSCs to stroma and increases tissue stemness; ROCK1 inhibitor (GSK269962A) curtails MSC migration and stromal differentiation (Li 2024; Cell Commun Signal; May 2024; https://doi.org/10.1186/s12964-024-01644-4) (li2024aberrantactivationof pages 1-3). - Oxidative stress therapy: Mitochondrial ROS blockade (anethole trithione) reduced prostate weight and voiding frequency, and suppressed proliferation/stemness in BPH-1 cells and organoids (dos Santos 2024; Am J Pathol; Jan 2024; https://doi.org/10.1016/j.ajpath.2023.09.010) (santos2024cellplasticityin pages 1-2). - Microbiome–inflammation axis: P. gingivalis detected in prostatic fluid of BPH with periodontitis; IL‑6 rose 4.47-fold, IL‑6Rα 5.74-fold, gp130 4.47-fold; P.g-LPS induced epithelial/stromal proliferation/fibrosis via IL‑6/IL‑6R/gp130→AKT signaling (Wang 2024; Mil Med Res; May 2024; https://doi.org/10.1186/s40779-024-00533-8) (fei2024integratingspatialtranscriptomics pages 15-15).

Current applications and real-world implementations - 5α-reductase inhibitors and α1-adrenergic blockers target androgen synthesis and smooth muscle tone (standard of care) while not directly addressing stromal induction or fibrosis; emerging preclinical strategies include ROCK inhibition (Y‑27632; GSK269962A) to reduce EMT/fibrosis and mitochondrial ROS inhibitors to reduce epithelial plasticity and hyperplasia (shan2024y27632targetingrock1&2 pages 1-2, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2). - Growth factor axis targeting: Spatially-resolved data nominating IGF1/IGF1R and CXCL13/CXCR5 as candidate stromal–epithelial crosstalk targets in human BPH (fei2024integratingspatialtranscriptomics pages 15-15). - Inflammation-focused strategies: Addressing oral–prostate axis and IL‑6/IL‑6R/gp130–AKT signaling may mitigate BPH progression in patients with periodontitis (fei2024integratingspatialtranscriptomics pages 15-15).

Expert opinions and analysis - The convergence of hypoxia-driven epithelial EMT, stromal IGF1/CXCL13 induction, and TGF‑β/ROCK-mediated fibrosis provides a unifying model that reconciles embryonic reawakening with chronic inflammation and metabolic stress. Single-cell/spatial data elevate BE5 hypoxic basal cells as initiators and clarify nodular heterogeneity. Mechanistic interventions (ROCK inhibition; mito-ROS blockade) show causal leverage on core phenotypes in vivo and ex vivo, supporting translation beyond symptom control to disease modification (fei2024integratingspatialtranscriptomics pages 15-15, shan2024y27632targetingrock1&2 pages 1-2, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2).

Relevant statistics and data - BE5 nodular initiator state: elevated hypoxia score and c-Fos; glandular nodules enriched for EMT/proliferation signatures versus stromal nodules (qualitative single-cell/spatial distinctions) (fei2024integratingspatialtranscriptomics pages 15-15, fei2024integratingspatialtranscriptomics pages 1-2). - IGF1 necessity: IGF1 required for BPH-1 spheroid and patient-derived organoid formation (functional requirement in vitro; qualitative) (fei2024integratingspatialtranscriptomics pages 15-15). - ROCK inhibition: Y‑27632 reduced β‑catenin (with MG132 attenuating the effect), downregulated c‑MYC/SNAI1/Survivin, decreased Ki‑67, increased TUNEL; lowered prostate index and collagen in testosterone-BPH rats (significance p<0.01–0.001; directionality and targets specified) (shan2024y27632targetingrock1&2 pages 7-11). - TGF‑β/ROCK1→MSC recruitment: GSK269962A (5 mg/kg, 4 weeks) suppressed MSC migration and stromal differentiation in vivo; p‑Smad2/3 expansion correlated with prostate size/inflammation (li2024aberrantactivationof pages 1-3). - Microbiome–IL‑6 axis: In rats, P. gingivalis infection increased epithelial thickness ~3-fold versus control and collagen fibrosis ~5-fold; IL‑6 (4.47×), IL‑6Rα (5.74×), gp130 (4.47×) upregulated; AKT activation implicated (fei2024integratingspatialtranscriptomics pages 15-15). - Oxidative stress therapy: anethole trithione decreased prostate weight and voiding frequency and suppressed epithelial proliferation/stemness in vitro and organoids (qualitative reductions) (santos2024cellplasticityin pages 1-2).

Core Pathophysiology (answers to objectives) - Primary mechanisms: reawakened stromal induction (IGF1/CXCL13), epithelial plasticity under hypoxia (FOS→EMT), TGF‑β/ROCK-driven fibrosis/myofibroblast activation, and inflammation (IL‑6/AKT), all localized to the TZ and coordinated across stroma and epithelium (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11, santos2024cellplasticityin pages 1-2). - Dysregulated pathways: TGF‑β/Smad and ROCK, WNT/β‑catenin, RTK/PI3K/AKT (IGF1), chemokine signaling (CXCL13/CXCR5), hypoxia/FOS, IL‑6/IL‑6R/gp130→AKT (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11). - Cellular processes: EMT, MSC recruitment and fibroblast/myofibroblast differentiation, ECM deposition, oxidative stress responses, epithelial lineage reprogramming (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2).

Key Molecular Players - Genes/Proteins: ROCK1/ROCK2, TGFB1, SMAD2/3, CTNNB1, MYC, SNAI1, IGF1/IGF1R, CXCL13/CXCR5, FOS, AR/SRD5A2 (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, shan2024y27632targetingrock1&2 pages 1-2, santos2024cellplasticityin pages 1-2). - Chemical entities: Y‑27632 (ROCK inhibitor), GSK269962A (ROCK1 inhibitor), anethole trithione (mito-ROS inhibitor); clinically used PDE5 inhibitor (tadalafil) has anti-fibrotic effects (outside the core evidence set) (shan2024y27632targetingrock1&2 pages 1-2, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2). - Cell types: BE5 basal epithelial cells; luminal/club-like epithelial intermediates; fibroblasts/myofibroblasts; MSCs (LepR+); macrophages and other immune cells (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2). - Anatomical locations: prostate transition zone, periurethral stroma (fei2024integratingspatialtranscriptomics pages 15-15, santos2024cellplasticityin pages 1-2).

Biological Processes (GO-style) - Positive regulation of epithelial cell proliferation; epithelial–mesenchymal transition; response to hypoxia; TGF‑β receptor signaling; WNT signaling; PI3K/AKT signaling; chemokine-mediated signaling; extracellular matrix organization; fibroblast migration and differentiation; response to oxidative stress (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, shan2024y27632targetingrock1&2 pages 1-2, santos2024cellplasticityin pages 1-2).

Cellular Components - Plasma membrane (IGF1R, CXCR5, IL‑6R/gp130); cytoplasm and nucleus (β‑catenin translocation; FOS nuclear activity); extracellular space (IGF1, CXCL13, TGF‑β) (fei2024integratingspatialtranscriptomics pages 15-15, shan2024y27632targetingrock1&2 pages 1-2, li2024aberrantactivationof pages 1-3).

Disease Progression (sequence) - Trigger(s): aging-associated stromal reawakening and hypoxia in TZ epithelium; microbial/inflammatory cues (IL‑6 axis) (fei2024integratingspatialtranscriptomics pages 15-15). - Early events: hypoxia-driven BE5 activation (FOS), stromal secretion of IGF1/CXCL13; recruitment of MSCs via TGF‑β/ROCK (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3). - Expansion phase: EMT and epithelial lineage reprogramming; myofibroblast activation and ECM deposition; WNT/β‑catenin and PI3K/AKT reinforce proliferation (shan2024y27632targetingrock1&2 pages 1-2, li2024aberrantactivationof pages 1-3, fei2024integratingspatialtranscriptomics pages 15-15). - Clinical phase: nodular enlargement in TZ → bladder outlet obstruction and LUTS; persistent inflammation and oxidative stress maintain disease (fei2024integratingspatialtranscriptomics pages 15-15, santos2024cellplasticityin pages 1-2).

Phenotypic Manifestations (HP terms) - Lower urinary tract symptoms (LUTS): urinary frequency, urgency, nocturia, weak stream, incomplete emptying (HP:0012590 series; mechanistic basis in TZ expansion and stromal tone) (fei2024integratingspatialtranscriptomics pages 15-15, santos2024cellplasticityin pages 1-2).

Gene/protein annotations with ontology terms - HGNC: ROCK1 (HGNC:10251), ROCK2 (HGNC:10252), TGFB1 (HGNC:11766), SMAD2 (HGNC:6767), SMAD3 (HGNC:6769), CTNNB1 (HGNC:2514), MYC (HGNC:7553), SNAI1 (HGNC:11128), IGF1 (HGNC:5463), IGF1R (HGNC:5465), CXCL13 (HGNC:10644), CXCR5 (HGNC:1643), FOS (HGNC:3796), AR (HGNC:644), SRD5A2 (HGNC:11284) (fei2024integratingspatialtranscriptomics pages 15-15, shan2024y27632targetingrock1&2 pages 1-2, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2).

Cell type involvement (CL terms) - Basal epithelial cell (BE5-like): CL:0002252; fibroblast: CL:0000057; myofibroblast: CL:0000186; macrophage: CL:0000235; T cell: CL:0000084 (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2).

Anatomical locations (UBERON terms) - Prostate transition zone: UBERON:0012369; prostate stroma: UBERON:0002369; prostatic urethra/periurethral region: UBERON:0001334 (fei2024integratingspatialtranscriptomics pages 15-15, santos2024cellplasticityin pages 1-2).

Chemical entities (ChEBI) - Y‑27632 (CHEBI:63608); GSK269962A (CHEBI:63634); anethole trithione (CHEBI:2249) (shan2024y27632targetingrock1&2 pages 1-2, li2024aberrantactivationof pages 1-3, santos2024cellplasticityin pages 1-2).

Evidence items (with URLs and dates) - Fei et al., 2024-04-10, J Transl Med: https://doi.org/10.1186/s12967-024-05212-9 (hypoxia→FOS; BE5; nodular EMT/proliferation) (fei2024integratingspatialtranscriptomics pages 15-15, fei2024integratingspatialtranscriptomics pages 1-2). - Pollack et al., 2024-01-11, JCI Insight: https://doi.org/10.1172/jci.insight.176479 (IGF1/CXCL13 stromal induction; IGF1 necessity for organoids) (fei2024integratingspatialtranscriptomics pages 15-15). - Shan et al., 2024-10-04, Mol Biomed: https://doi.org/10.1186/s43556-024-00216-9 (ROCK1/2→β-catenin/TGF‑β; Y‑27632 reverses fibrosis/EMT/proliferation; in vivo rat data) (shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11). - Li et al., 2024-05-23, Cell Commun Signal: https://doi.org/10.1186/s12964-024-01644-4 (TGF‑β/ROCK1 recruits MSCs; GSK269962A blocks stromal hyperplasia) (li2024aberrantactivationof pages 1-3). - Dos Santos et al., 2024-01-01, Am J Pathol: https://doi.org/10.1016/j.ajpath.2023.09.010 (epithelial plasticity; mitochondrial ROS inhibitor reduces prostate weight and LUTS proxy) (santos2024cellplasticityin pages 1-2). - Wang et al., 2024-05-17, Mil Med Res: https://doi.org/10.1186/s40779-024-00533-8 (oral–prostate axis; IL‑6/IL‑6R/gp130→AKT; fold-changes and histologic effects) (fei2024integratingspatialtranscriptomics pages 15-15).

Embedded artifact | Category | Entity | Standard ID | Role / Mechanism in BPH | Evidence (year) | Citation DOI/URL | |---|---|---:|---|---:|---| | Pathway | TGF-β / ROCK1 axis | TGFB1 (HGNC:11766); ROCK1 (HGNC:10251) | Aberrant TGF-β activation engages ROCK1 to recruit LepR+ MSCs → differentiation to myofibroblasts, stromal hyperplasia; ROCK1 inhibition (GSK269962A) suppresses MSC migration and stromal expansion | 2024 (li2024aberrantactivationof pages 1-3) | https://doi.org/10.1186/s12964-024-01644-4 | | Pathway | WNT / β-catenin signaling | CTNNB1 (HGNC:2514) | ROCK1/2 activity stabilizes β-catenin, driving EMT and proliferation; Y-27632 reduces β-catenin levels and downstream targets (c-MYC, Snail, Survivin) | 2024 (shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11) | https://doi.org/10.1186/s43556-024-00216-9 | | Pathway | PI3K/AKT signaling | PIK3CA (HGNC:8975) / AKT (family) | RTK activation (e.g., stromal IGF1/CSF1) signals through PI3K/AKT to promote epithelial proliferation and survival in BPH nodules | 2024 (li2024aberrantactivationof pages 1-3, fei2024integratingspatialtranscriptomics pages 15-15) | https://doi.org/10.1186/s12964-024-01644-4 | | Process / Program | Epithelial–mesenchymal transition (EMT) | SNAI1 (HGNC:11128) | TGF-β and hypoxia-driven programs induce EMT in epithelial cells → myofibroblast-like phenotypes, ECM deposition and nodular formation | 2024 (fei2024integratingspatialtranscriptomics pages 15-15, shan2024y27632targetingrock1&2 pages 1-2) | https://doi.org/10.1186/s12967-024-05212-9 ; https://doi.org/10.1186/s43556-024-00216-9 | | Pathway / TF | Hypoxia → FOS (c-Fos) activation | FOS (HGNC:3796) | Hypoxia-enriched BE5 basal epithelial cells upregulate FOS → promotes hypoxia-induced EMT and proliferative nodular initiation in the transition zone | 2024 (fei2024integratingspatialtranscriptomics pages 15-15, fei2024integratingspatialtranscriptomics pages 1-2) | https://doi.org/10.1186/s12967-024-05212-9 | | Stromal induction | IGF1 / CXCL13 stromal factors | IGF1 (HGNC:5463); CXCL13 (HGNC:10644); IGF1R (HGNC:5465); CXCR5 (HGNC:1643) | BPH fibroblasts secrete IGF1 and CXCL13 that act on adjacent epithelium (IGF1R/CXCR5) to induce ductal proliferation and organoid growth (stromal→epithelial induction) | 2024 (fei2024integratingspatialtranscriptomics pages 15-15) | https://doi.org/10.1172/jci.insight.176479 (Pollack 2024) | | Gene / Effector | ROCK2 | ROCK2 (HGNC:10252) | ROCK2 upregulated in BPH stroma/epithelium; promotes fibrosis, EMT and cell proliferation via β-catenin and TGF-β cross-talk; inhibited by Y-27632 | 2024 (shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11) | https://doi.org/10.1186/s43556-024-00216-9 | | Gene / Effector | TGFB1 (TGF-β1) | TGFB1 (HGNC:11766) | Core profibrotic cytokine driving myofibroblast activation, ECM deposition and EMT in BPH stroma | 2024 (li2024aberrantactivationof pages 1-3, shan2024y27632targetingrock1&2 pages 1-2) | https://doi.org/10.1186/s12964-024-01644-4 | | Gene / Effector | CTNNB1 (β-catenin) | CTNNB1 (HGNC:2514) | Mediates WNT-driven transcriptional programs (c-MYC, SNAI1) supporting proliferation and EMT in hyperplastic prostate | 2024 (shan2024y27632targetingrock1&2 pages 1-2) | https://doi.org/10.1186/s43556-024-00216-9 | | Gene / Effector | MYC (c-MYC) | MYC (HGNC:7553) | Downstream of β-catenin/WNT and promotes epithelial proliferation in BPH nodules | 2024 (shan2024y27632targetingrock1&2 pages 1-2) | https://doi.org/10.1186/s43556-024-00216-9 | | Gene / Effector | SMAD2 / SMAD3 | SMAD2 (HGNC:6767); SMAD3 (HGNC:6769) | Canonical mediators of TGF-β signaling; p-Smad2/3 increased in hyperplastic stroma correlating with volume/inflammation | 2024 (li2024aberrantactivationof pages 1-3) | https://doi.org/10.1186/s12964-024-01644-4 | | Gene / Effector | FOS (c-Fos) | FOS (HGNC:3796) | Transcriptional effector induced by hypoxia in BE5 cells; links hypoxia → EMT/proliferation in nodular formation | 2024 (fei2024integratingspatialtranscriptomics pages 15-15) | https://doi.org/10.1186/s12967-024-05212-9 | | Gene / Effector | AR / SRD5A2 (androgen axis) | AR (HGNC:644); SRD5A2 (HGNC:11284) | Intraprostatic DHT–AR signaling modulates growth; androgen-independent epithelial populations also expand in BPH models (cell plasticity) | 2023–2024 (santos2024cellplasticityin pages 1-2, fei2024integratingspatialtranscriptomics pages 15-15) | https://doi.org/10.1016/j.ajpath.2023.09.010 | | Cell type | Basal epithelial (BE5-like) | basal epithelial cell (CL:0002252) | BE5 identified as initiating/transitional cell (LE→BE) with hypoxia/FOS signature driving glandular nodular formation | 2024 (fei2024integratingspatialtranscriptomics pages 15-15, fei2024integratingspatialtranscriptomics pages 1-2) | https://doi.org/10.1186/s12967-024-05212-9 | | Cell type | Club-like luminal / intermediate cells | club cell (CL:0000061) (annotated) | Androgen-independent / club-like populations expand in BPH and show altered proliferation and antioxidant vulnerability | 2024 (santos2024cellplasticityin pages 1-2) | https://doi.org/10.1016/j.ajpath.2023.09.010 | | Cell type | Fibroblast | fibroblast (CL:0000057) | Stromal fibroblasts secrete inductive factors (IGF1, CXCL13) and ligands (CSF1/IL34) that drive epithelial proliferation and activate RTK/PI3K signaling | 2024 (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3) | https://doi.org/10.1172/jci.insight.176479 ; https://doi.org/10.1186/s12964-024-01644-4 | | Cell type | Myofibroblast | myofibroblast (CL:0000186) | Main ECM-producing cell in BPH fibrosis; arises from MSC recruitment and stromal differentiation under TGF-β/ROCK signaling | 2024 (li2024aberrantactivationof pages 1-3) | https://doi.org/10.1186/s12964-024-01644-4 | | Cell type | Macrophage | macrophage (CL:0000235) | Infiltrating macrophage subsets (lipid-rich/TREM2+ in large prostates) interact with stroma and promote proliferation/fibrosis (immune–stromal crosstalk) | 2024–2025 (lanman2025immunedysregulationin pages 8-11, santos2024cellplasticityin pages 1-2) | https://doi.org/10.1016/j.ajpath.2023.09.010 | | Anatomy | Prostate transition zone | UBERON:0012369 | Anatomical nidus of nodular hyperplasia and LUTS; site of epithelial–stromal reawakening and nodular formation | 2024 (fei2024integratingspatialtranscriptomics pages 15-15, santos2024cellplasticityin pages 1-2) | https://doi.org/10.1186/s12967-024-05212-9 ; https://doi.org/10.1016/j.ajpath.2023.09.010 | | Anatomy | Prostate stroma | UBERON:0002369 | Location of fibroblast/myofibroblast expansion, ECM remodeling and secreted inductive signals in BPH | 2024 (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3) | https://doi.org/10.1172/jci.insight.176479 ; https://doi.org/10.1186/s12964-024-01644-4 | | Anatomy | Prostatic urethra (periurethral region) | UBERON:0001334 | Periurethral (transition) anatomy explains clinical BOO/LUTS when nodules enlarge the TZ | 2024 (fei2024integratingspatialtranscriptomics pages 15-15) | https://doi.org/10.1186/s12967-024-05212-9 | | Chemical / Drug | Y-27632 (ROCK inhibitor) | CHEBI:63608 | Pharmacologic ROCK1/2 inhibition reduces β-catenin stability, TGF-β signaling, fibrosis, EMT and cell proliferation in BPH models | 2024 (shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11) | https://doi.org/10.1186/s43556-024-00216-9 | | Chemical / Drug | GSK269962A (ROCK1 inhibitor) | CHEBI:63634 | Small-molecule ROCK1 inhibitor (preclinical) reduces MSC recruitment and stromal differentiation in vivo (therapeutic proof-of-concept) | 2024 (li2024aberrantactivationof pages 1-3) | https://doi.org/10.1186/s12964-024-01644-4 | | Chemical / Drug | Anethole trithione (mito-ROS inhibitor) | CHEBI:2249 | Mitochondrial ROS inhibition decreased prostate weight, voiding frequency and epithelial proliferation in Pb-PRL BPH mouse model (antioxidant therapeutic effect) | 2024 (santos2024cellplasticityin pages 1-2) | https://doi.org/10.1016/j.ajpath.2023.09.010 | | Chemical / Drug | Tadalafil (PDE5 inhibitor) | CHEBI:9392 | Reported to reduce prostatic fibrosis via miR-3126-3p/FGF9 axis in prostatic stromal models (anti-fibrotic mechanism) | 2024 (related literature) | https://doi.org/10.1186/s13062-024-00504-y |

Table: A compact ontology-ready table mapping key pathways, genes/proteins (HGNC), cell types (CL), anatomical sites (UBERON), and chemicals (ChEBI) to concise mechanisms in BPH with 2023–2024 evidence and DOI/URL references; citations reference extracted evidence (context IDs) from recent studies (shan2024y27632targetingrock1&2 pages 1-2, fei2024integratingspatialtranscriptomics pages 1-2).

Direct quotes (selected) - “A distinct subgroup of basal epithelial (BE5) cells… play a crucial role in driving this progression through the hypoxia-induced epithelial–mesenchymal transition (EMT) signaling pathway… c-Fos expression… closely related to hypoxia and cell proliferation” (Fei 2024) (fei2024integratingspatialtranscriptomics pages 1-2). - “The top stromal factors were insulin-like growth factor 1 (IGF1) and CXC chemokine ligand 13 (CXCL13)… IGF1 is necessary for the generation of BPH-1 cell spheroids and patient-derived BPH cell organoids” (Pollack 2024) (fei2024integratingspatialtranscriptomics pages 15-15). - “ROCK1 and ROCK2 were significantly upregulated in BPH tissues… Y-27632… inhibited cell proliferation, fibrosis, epithelial–mesenchymal transition… ROCK downregulation inhibited the β-catenin signaling pathway… and TGF‑β/Smad2/3 signaling… reversed prostatic hyperplasia and fibrosis in BPH model rats” (Shan 2024) (shan2024y27632targetingrock1&2 pages 7-11). - “Aberrant activation of transforming growth factor β (TGF‑β)/Rho kinase 1 (ROCK1) increased the stemness of BPH tissue by recruiting mesenchymal stem cells (MSCs)… inhibition of ROCK1 activation suppressed MSC migration and their potential for stromal differentiation” (Li 2024) (li2024aberrantactivationof pages 1-3). - “P. gingivalis… infection… upregulated the expression of interleukin‑6 (IL‑6; 4.47‑fold), interleukin‑6 receptor‑α (IL‑6Rα; 5.74‑fold) and glycoprotein 130 (gp130; 4.47‑fold)… activates the Akt pathway… induces BPH” (Wang 2024) (fei2024integratingspatialtranscriptomics pages 15-15).

Limitations - Some quantitative effect sizes (e.g., exact percent changes for in vivo prostate index) are reported qualitatively in the retrieved excerpts; deeper extraction from full texts would refine numerical precision. Nevertheless, the directional findings and core mechanisms are consistently supported across independent 2024 studies. (shan2024y27632targetingrock1&2 pages 7-11, fei2024integratingspatialtranscriptomics pages 15-15).

Conclusion BPH progression in the transition zone reflects an interplay between hypoxia‑driven epithelial EMT and plasticity (BE5, FOS), stromal induction (IGF1/CXCL13), and TGF‑β/ROCK‑mediated fibrosis that recruits and differentiates MSCs, reinforced by inflammatory IL‑6→AKT signaling and oxidative stress. These insights nominate actionable targets—ROCK1/2, IGF1/IGF1R, IL‑6/IL‑6R/gp130, and mitochondrial ROS—with preclinical evidence for disease modification alongside standard symptomatic therapies. (fei2024integratingspatialtranscriptomics pages 15-15, li2024aberrantactivationof pages 1-3, shan2024y27632targetingrock1&2 pages 1-2, shan2024y27632targetingrock1&2 pages 7-11, santos2024cellplasticityin pages 1-2)

References

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  7. (lanman2025immunedysregulationin pages 8-11): Nadia A. Lanman, Meaghan M. Broman, Harish Kothandaraman, Gregory M. Cresswell, Gada D. Awdalkreem, Dilinaer Wusiman, Andree K. Kolliegbo, Alexander P. Glaser, Brian T. Helfand, Renee E. Vickman, Jiang Yang, Simon W. Hayward, and Timothy L. Ratliff. Immune dysregulation in the prostates of c57bl/6aire-/-mice mirrors that seen in human benign prostatic hyperplasia. BioRxiv, Aug 2025. URL: https://doi.org/10.1101/2025.08.12.669857, doi:10.1101/2025.08.12.669857. This article has 0 citations and is from a poor quality or predatory journal.