A conserved mechanism module for the sixth hallmark of cancer (Hanahan & Weinberg): activation of invasion and metastasis, the multistep invasion-metastasis cascade that accounts for the great majority of cancer deaths. The conserved causal chain runs from activation of an epithelial-mesenchymal transition (EMT) program - loss of E-cadherin and cell-cell junctions, acquisition of a motile, invasive mesenchymal phenotype driven by EMT transcription factors (SNAIL, SLUG, ZEB1/2, TWIST) - through local invasion across the basement membrane and stroma via matrix-degrading proteases (MMPs), into intravasation, survival in the circulation as circulating tumor cells, extravasation at a distant site, and finally metastatic colonization, the rate-limiting step in which disseminated cells adapt to the foreign microenvironment and resume proliferation (often after a period of dormancy). Individual disorder entries declare conformance via conforms_to, substituting tumor-type-specific drivers and organotropic patterns (e.g., bone-tropic breast cancer, liver-tropic colorectal cancer). This module connects to tumor_angiogenesis (vasculature provides the route for dissemination) and tumor_promoting_inflammation (stromal cells facilitate invasion).
4 nodes
0 cell types
5 processes
2 disorders
A conserved antifungal drug-choice-gating module representing the species-level intrinsic resistance that excludes whole antifungal classes a priori, before any susceptibility testing. Unlike the fungal drug-target modules (ergosterol synthesis, ergosterol-membrane binding, glucan-synthase, nucleic-acid antimetabolite), the nodes here are not a single druggable enzyme but a gating principle: the small antifungal armamentarium is sharply constrained by organism identity, because the target a class needs is absent, divergent, or non-viable in certain fungi. The paradigm cases are fixed by phylogeny — Aspergillus is intrinsically resistant to fluconazole (requiring a mold-active azole such as voriconazole or isavuconazole, or amphotericin B); Cryptococcus is intrinsically resistant to the echinocandins (the β-1,3-glucan-synthase target is present but not a viable drug target); and the Mucorales (mucormycosis) are intrinsically resistant to both voriconazole and the echinocandins, leaving amphotericin B or isavuconazole. Layered on top of this fixed intrinsic landscape, emerging multidrug-resistant species — most notably Candida auris — acquire resistance across the azoles, polyenes, and echinocandins simultaneously, further narrowing empiric options. This module encodes WHY empiric antifungal selection depends on organism identification rather than on "any antifungal," complementing the target-based modules that explain how a given drug works once a viable target exists.
2 nodes
0 cell types
1 process
0 disorders
Used By
No disorder entries currently reference this module.
A conserved mechanism module representing the three principal RNA-targeting paradigms by which antisense oligonucleotides (ASOs) — single-stranded nucleic acids that target RNA — produce therapeutic effects. The first paradigm is RNase H-mediated mRNA degradation, used when the therapeutic goal is to reduce a pathogenic or overexpressed protein (dominant gain-of-function diseases and dyslipidemias). The second paradigm is splice-site occlusion, in which the ASO sterically blocks a splice regulatory element to redirect spliceosome activity — either forcing exon skipping to restore a disrupted reading frame (e.g., DMD exon-skipping ASOs), or unblocking exon inclusion to restore functional protein (e.g., nusinersen in SMA). The third paradigm is steric translation blockade, in which the ASO physically impedes ribosomal access without recruiting RNase H (used in fomivirsen, the first FDA-approved ASO). Each paradigm operates on a distinct pre-RNA or mRNA target and leaves a distinct molecular footprint. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific gene, transcript, protein, and variant while preserving the shared RNA-level causal chain.
8 nodes
0 cell types
7 processes
0 disorders
Used By
No disorder entries currently reference this module.
A conserved pathological module representing the shared core of the heritable thoracic aortic aneurysm and dissection (TAAD) syndromes. A primary genetic defect in an aortic wall component — extracellular matrix microfibrils/elastic fibers (FBN1, COL3A1, and other matrix genes), the vascular smooth muscle cell contractile apparatus (ACTA2, MYH11, MYLK, PRKG1), or the TGF-beta signaling pathway itself (TGFBR1/2, SMAD3, TGFB2/3, SKI) — converges on dysregulated, paradoxically increased TGF-beta signaling in the aortic media. Excess TGF-beta signaling together with the underlying structural defect drives medial degeneration (smooth muscle cell depletion and elastic fiber fragmentation with disordered matrix), progressively weakening the aortic wall so that it dilates and ultimately dissects or ruptures. This conserved core is shared across the syndromic aortopathies (Marfan, Loeys-Dietz, vascular Ehlers-Danlos, Shprintzen-Goldberg, arterial tortuosity) and nonsyndromic familial TAAD. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific causal gene/lesion while preserving the conserved defect -> TGF-beta dysregulation -> medial degeneration -> dilation -> dissection chain.
5 nodes
1 cell type
3 processes
7 disorders
Conserved cortical malformation mechanism in which disruption of radial-glial apical attachment, ventricular-lining integrity, cadherin/catenin trafficking, ciliogenesis, actin scaffolding, or apical progenitor signaling produces periventricular nodules or related heterotopia. The shared skeleton is apical-neuroependyma perturbation followed by ventricular lining breaks or apical detachment, mislocalized progenitors or ectopic periventricular neurogenesis, and secondary neuronal positioning or migration abnormalities. This module is intended for FLNA-related PVH, ARFGEF2-related PVH with microcephaly, FAT4/DCHS1-related Van Maldergem/PVH mechanisms, and selected rare PVH branches where apical radial-glial or neuroependymal failure is central.
7 nodes
4 cell types
11 processes
1 disorder
A conserved developmental-patterning module, the axial counterpart of the limb/digit and pharyngeal-arch serial-homology modules. The vertebrae and ribs are serially repeated (metameric) elements derived from somites, which bud off the presomitic mesoderm one pair at a time under the control of the segmentation clock — an oscillator built from coupled Notch, Wnt, and FGF signaling — interacting with a posterior-to-anterior FGF/Wnt determination wavefront. Because the same periodic mechanism builds every segment, a single lesion in the clock or its Notch components (DLL3, MESP2, LFNG, HES7, TBX6) perturbs many segments at once and produces a coordinated multi-segment malformation bundle — multiple hemivertebrae, fused/block vertebrae, and rib fusions or malalignment across the axial skeleton — rather than an isolated single-segment defect. The spondylocostal/spondylothoracic dysostoses and related congenital vertebral malsegmentation disorders differ in the specific Notch-pathway gene but converge on this clock-to-malsegmentation chain. Conforming disorder entries declare conformance via conforms_to, substituting the disorder-specific segmentation-clock gene while preserving the perturbed-segmentation-to-serially-homologous-malsegmentation chain.
3 nodes
3 cell types
5 processes
3 disorders
A conserved antibacterial drug-mechanism module representing the bacterial peptidoglycan cell-wall biosynthesis pathway that cell-wall-active antibiotics target. Across most clinically important bacteria, cytoplasmic and membrane-associated enzymes build peptidoglycan precursors and the lipid II carrier, glycosyltransferases polymerize the glycan strands, and penicillin-binding protein (PBP) transpeptidases cross-link the peptide stems into the load-bearing sacculus. Cell-wall-active drugs interrupt distinct steps of this conserved pathway: beta-lactams (penicillins, cephalosporins, carbapenems, monobactams) acylate the PBP transpeptidase active site; glycopeptides (vancomycin, teicoplanin) sequester the D-Ala-D-Ala terminus of lipid II; fosfomycin, cycloserine, and bacitracin block precursor and carrier steps. Because peptidoglycan is essential and unique to bacteria, its inhibition triggers autolysin-mediated lysis and is selectively bactericidal. This module defines the mechanism-of-action design pattern for cell-wall-active antibiotic treatments: conforming bacterial-disease entries link a treatment to the specific node it inhibits via target_mechanisms. It also encodes why drug choice is mechanism-dependent — organisms that lack peptidoglycan (e.g. Mycoplasma) have no target and are intrinsically resistant, and acquired resistance (beta-lactamase, altered PBPs such as PBP2a, D-Ala-D-Lac remodeling) protects the pathway from specific agents.
5 nodes
0 cell types
4 processes
13 disorders
A conserved antibacterial drug-mechanism module representing the bacterial type II topoisomerases — DNA gyrase (GyrA/GyrB) and topoisomerase IV (ParC/ParE) — that manage chromosomal supercoiling and decatenation during replication. Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin) are the major drug class acting here: they trap the enzyme-DNA cleavage complex, converting the topoisomerase into a DNA-damaging agent that generates double-strand breaks and is bactericidal. Because gyrase and topoisomerase IV are bacterial enzymes distinct from human topoisomerases, fluoroquinolones are selectively toxic. This module defines the mechanism-of-action design pattern for fluoroquinolone treatments: conforming entries link a treatment to the gyrase/ topoisomerase target via target_mechanisms. It also encodes the quinolone-resistance-determining-region (QRDR) mutation and efflux resistance that gate fluoroquinolone use.
2 nodes
0 cell types
2 processes
2 disorders
A conserved antibacterial drug-mechanism module representing the bacterial de novo tetrahydrofolate (THF) biosynthesis pathway, which bacteria must build themselves because — unlike humans — they cannot take up preformed folate from the diet. Two sequential enzymes are antibacterial targets: dihydropteroate synthase (DHPS), inhibited by the sulfonamides (sulfamethoxazole, dapsone), and dihydrofolate reductase (DHFR), inhibited by trimethoprim. Blocking THF synthesis starves the cell of the one-carbon donors needed for nucleotide and amino-acid synthesis. Combining a DHPS inhibitor with a DHFR inhibitor (co-trimoxazole = trimethoprim-sulfamethoxazole) produces sequential blockade with synergistic, bactericidal activity. DHPS is unique to prokaryotes, giving selectivity. This module defines the mechanism-of-action design pattern for antifolate treatments: conforming entries link a treatment to the DHPS/DHFR target via target_mechanisms.
2 nodes
0 cell types
2 processes
2 disorders
A conserved antibacterial drug-mechanism module representing bacterial mRNA translation by the 70S ribosome — the second major antibiotic target after the cell wall. Multiple antibiotic classes inhibit distinct steps: aminoglycosides and tetracyclines act on the 30S subunit (decoding/A-site tRNA), while macrolides, lincosamides (clindamycin), chloramphenicol, and oxazolidinones (linezolid) act on the 50S subunit (peptidyl transferase centre and polypeptide exit tunnel). Most are bacteriostatic (translational arrest), but aminoglycosides are bactericidal because they cause misreading and membrane damage. A clinically important consequence distinct from killing is suppression of toxin and exoprotein synthesis: protein-synthesis inhibitors such as clindamycin and linezolid shut off production of secreted toxins even at the high bacterial densities where beta-lactams lose efficacy (the inoculum/Eagle effect), which is why they are added in toxin-mediated streptococcal and staphylococcal disease. This module defines the mechanism-of-action design pattern for ribosome-targeting treatments: conforming entries link a treatment to the node it inhibits via target_mechanisms.
3 nodes
0 cell types
3 processes
12 disorders
A conserved antibacterial drug-mechanism module representing bacterial DNA-dependent RNA polymerase (RNAP), the enzyme that transcribes mRNA and the target of the rifamycin class (rifampicin, rifabutin, rifapentine, rifaximin). Rifamycins bind the RNAP beta subunit (encoded by rpoB) in the DNA/RNA channel and block extension of nascent RNA beyond a few nucleotides, halting transcription. Because the bacterial RNAP sequence diverges from the human enzyme, rifamycins are selectively toxic. Rifamycins penetrate cells and biofilms well and are a backbone of antimycobacterial therapy and of regimens for intracellular and device-associated infection — but because single rpoB point mutations confer high-level resistance, they are almost always used in combination. This module defines the mechanism-of-action design pattern for rifamycin treatments: conforming entries link a treatment to the RNAP target via target_mechanisms.
2 nodes
0 cell types
2 processes
2 disorders
A conserved pathophysiology module representing the molecular machine that the "BBSome-opathies" share: assembly and membrane-coupled trafficking of the BBSome, an obligate eight-subunit complex that escorts signaling receptors and other cargo into and out of the primary cilium. The module is deliberately scoped to the BBSome machine itself - its core subunits (BBS1, BBS2, BBS4, BBS5, BBS7, TTC8/BBS8, BBS9, BBIP1/BBS18), its chaperonin-like assembly factors (MKKS/BBS6, BBS10, BBS12), and its dedicated operators ARL6/BBS3 (the membrane-recruiting GTPase) and LZTFL1/BBS17 (a trafficking regulator) - and NOT the broader ciliary infrastructure (general IFT-B trains, transition-zone and basal-body proteins) that the wider ciliopathy spectrum also uses. Those belong to the ciliopathy_dysfunction module. Conforming disorder entries (e.g. Bardet-Biedl syndrome, McKusick-Kaufman syndrome, and BBSome-machine non-syndromic retinitis pigmentosa) declare conformance on their proximal pathophysiology nodes and then attach disorder-specific downstream organ branches: a disease differs from its siblings chiefly in WHICH cilia-dependent organ branches cross the clinical threshold.
5 nodes
0 cell types
2 processes
3 disorders
A conserved cardiac electrophysiology mechanism module for inherited arrhythmia syndromes (channelopathies) in structurally normal hearts. Pathogenic variants in cardiac ion channels or calcium-handling proteins shift the balance of depolarizing and repolarizing currents and disturb sarcoplasmic-reticulum calcium handling. This alters cardiomyocyte action potential duration (APD) and/or diastolic calcium, generating afterdepolarization-driven triggered activity (early afterdepolarizations from prolonged APD; delayed afterdepolarizations from calcium leak). Regional heterogeneity of repolarization and conduction creates an arrhythmogenic substrate that supports reentrant and triggered ventricular tachyarrhythmia (torsade de pointes, polymorphic ventricular tachycardia, ventricular fibrillation), clinically manifesting as syncope and sudden cardiac death. A parallel branch captures the same ion-channel and pacemaker machinery acting in the sinoatrial node, where loss of function produces bradyarrhythmia and sinus arrest rather than tachyarrhythmia.
6 nodes
2 cell types
6 processes
9 disorders
A conserved cardiac pathophysiology module representing the maladaptive remodeling pathway that underlies structural and contractile cardiomyopathy (HP:0001638, MONDO:0004994) across dilated, hypertrophic, and secondary forms. A primary cardiomyocyte insult — an inherited sarcomere or cytoskeletal protein defect, or an acquired hemodynamic, metabolic, toxic, or inflammatory stress — impairs contractile performance. The failing myocardium activates neurohormonal axes (renin-angiotensin-aldosterone and sympathetic) that initially compensate but chronically drive myocyte hypertrophy, cardiomyocyte loss, cardiac fibroblast activation, interstitial fibrosis, and chamber dilation or wall thickening. This adverse ventricular remodeling produces progressive systolic and/or diastolic contractile dysfunction, culminating in structural cardiac impairment and heart failure. This module is distinct from electrical/channelopathy disease (covered by cardiac_ion_channel_repolarization); it captures the structural/contractile final common pathway. Individual disorder entries declare conformance via conforms_to, substituting disorder-specific primary lesions (e.g., MYH7/MYBPC3 sarcomere variants in hypertrophic cardiomyopathy, TTN truncations or LMNA/desmosomal defects in dilated cardiomyopathy, infiltrative or toxic injury in secondary cardiomyopathy) while preserving the conserved chain.
5 nodes
2 cell types
9 processes
5 disorders
A conserved cerebellar neurodegeneration module representing the final common pathway by which functionally diverse insults converge on cerebellar Purkinje cell dysfunction, degeneration, and cerebellar ataxia. An initiating genetic (e.g., polyglutamine repeat-expansion proteotoxicity, ion-channel or calcium-handling defect), metabolic, mitochondrial/DNA-repair, or toxic insult stresses cerebellar neurons; this perturbs Purkinje cell intracellular calcium homeostasis and proteostasis, activates toxic cascades that drive Purkinje neuron apoptosis and loss, abolishes the cerebellar cortical output normally conveyed by Purkinje cells to the deep cerebellar nuclei, and produces progressive gait, limb, and speech incoordination. The module captures the shared core spanning the spinocerebellar ataxias (including polyglutamine SCAs), autosomal recessive ataxias, and acquired cerebellar degeneration. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific molecular lesion while preserving the conserved Purkinje-centered causal chain.
5 nodes
1 cell type
4 processes
2 disorders
A conserved module representing the final common pathway of cholesterol gallstone formation, the dominant form of cholelithiasis. Hepatic hypersecretion of cholesterol relative to bile salts and phospholipids produces gallbladder bile that is supersaturated with cholesterol. Within this metastable bile, pronucleating mucin and gallbladder factors accelerate the precipitation of solid cholesterol monohydrate crystals, while gallbladder hypomotility and bile stasis provide the residence time needed for crystals to be retained, aggregate, and grow into macroscopic gallstones. The resulting stones cause biliary colic, cystic-duct or biliary obstruction, and cholecystitis. Diverse predisposing factors (ABCG5/G8 and ABCB4 lithogenic variants, obesity, insulin resistance, female sex, rapid weight loss) converge on this supersaturation-nucleation-stasis triad. Conforming disorder entries substitute disorder-specific lithogenic drivers while preserving the conserved causal chain.
5 nodes
2 cell types
4 processes
0 disorders
Used By
No disorder entries currently reference this module.
A conserved developmental and degenerative module for the ciliopathies. Diverse upstream lesions in genes encoding basal body, transition zone, and intraflagellar transport (IFT) components disrupt the assembly, gating, and cargo trafficking of the primary cilium. Because the cilium is the cell's signaling antenna, these defects converge on impaired cilium-dependent signal transduction, principally Hedgehog (smoothened) signaling and non-canonical Wnt / planar cell polarity (PCP) signaling. The shared signaling failure is read out differently in each ciliated tissue, producing the pleiotropic, multisystem phenotype that unites Bardet-Biedl, Joubert, nephronophthisis, Jeune, Alstrom, Meckel, orofaciodigital, and short-rib polydactyly syndromes: retinal degeneration, cystic-fibrotic kidney disease, skeletal dysplasia with polydactyly, cerebellar/CNS malformation, and metabolic dysfunction. A parallel motile-cilia arm captures the distinct mechanism of primary ciliary dyskinesia, in which axonemal motility defects impair mucociliary clearance and left-right body patterning. Disorder entries reference these nodes via conforms_to and substitute gene- and organ-specific cell types and lesions.
10 nodes
7 cell types
9 processes
26 disorders
A conserved mechanism module representing isolated cytochrome c oxidase (COX, mitochondrial respiratory chain Complex IV) deficiency. Loss of a structural subunit, an assembly/maturation factor, a copper-delivery metallochaperone, or a heme A biosynthesis enzyme prevents maturation of a functional COX holoenzyme. The resulting block in terminal electron transfer (cytochrome c to molecular oxygen) and proton pumping collapses oxidative ATP synthesis, forcing anaerobic glycolysis (lactic acidosis) and producing energy failure in high-demand tissues (brain, heart, skeletal muscle, liver). The module captures the gene-agnostic core shared across the many nuclear and mtDNA causes of isolated COX deficiency; conforming disorder entries substitute the specific gene, the affected assembly sub-step, and the organ/tissue tropism while preserving this causal chain.
4 nodes
0 cell types
7 processes
23 disorders
A conserved final-common-pathway module for the congenital disorders of glycosylation (CDG) — the large, genetically heterogeneous family of inborn errors of protein glycosylation. Individual CDG arise from defects at mechanistically distinct points of the N-glycosylation machinery, but converge on a single shared lesion: hypoglycosylation of many client glycoproteins, which then produces a recurrent multisystem (neurologic, hepatic, coagulation, immune, dysmorphic, skeletal) disease. The family splits into two arms that share the hypoglycosylation hub but differ in where the machinery fails: (1) the type I disorders, in which assembly of the dolichol-linked (lipid-linked) oligosaccharide precursor in the endoplasmic reticulum is impaired (e.g. ALG9, ALG12, MPDU1, DOLK/DK1), so that truncated precursors are transferred to protein; and (2) the type II disorders, in which the glycan is assembled but its Golgi processing or the trafficking of the Golgi glycosylation machinery is defective (e.g. MGAT2 branching-enzyme deficiency, COG-complex disorders COG1/COG7), impairing maturation of complex N-glycans and, for the COG disorders, combined N- and O-glycosylation. Conforming disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific enzyme/complex lesion and arm while preserving the conserved defect -> hypoglycosylation -> multisystem chain.
4 nodes
3 cell types
6 processes
9 disorders
A conserved pathological module representing cellular senescence (GO:0090398) - a stress-induced, essentially permanent cell-cycle arrest - as a shared driver of age-related tissue dysfunction across organs. Diverse senescence-inducing stresses (replicative/telomeric, oncogenic, genotoxic, oxidative) engage the p16INK4a/Rb and p53/p21 tumor-suppressor programs to arrest the cell; arrested cells acquire a senescence-associated secretory phenotype (SASP) of proinflammatory cytokines, chemokines, and proteases; when immune clearance is outpaced, senescent cells accumulate, and their persistent secretome drives chronic inflammation, loss of regenerative capacity, and progressive tissue dysfunction. This is the conserved core that recurs in osteoarthritis, pulmonary and other organ fibrosis, atherosclerosis, and broader aging biology. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the tissue-specific senescent cell type (e.g. chondrocyte in osteoarthritis, fibroblast in pulmonary fibrosis) while preserving the conserved arrest -> SASP -> accumulation -> dysfunction chain.
5 nodes
1 cell type
6 processes
1 disorder
A conserved pathological module representing the dysregulation of normal wound healing (GO:0042060) that underlies organ fibrosis across tissues. Tissue injury triggers inflammation and resident mesenchymal cell activation, leading to myofibroblast transdifferentiation, excessive extracellular matrix deposition, and progressive architectural distortion with organ dysfunction. This module captures the shared core of fibrotic disease across liver, lung, heart, kidney, skin, and other organs. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting organ-specific cell types and anatomical locations while preserving the conserved causal chain and signaling axes.
5 nodes
3 cell types
7 processes
11 disorders
A conserved tumor-suppressive module representing the original, protective arm of cellular senescence (GO:0090398): in cells at risk of malignant transformation, oncogenic, replicative, and genotoxic stress engages the p16INK4a/Rb and p53/p21 programs to impose a permanent senescence-associated arrest that halts proliferation of premalignant cells and acts as a barrier to malignant transformation. A convergent, later-life thread is the aging-associated decline of stem-cell fitness (loss of stemness), which further limits the tumor-initiating capacity of aged tissue. This module is the deliberate complement of `cellular_senescence`, which models the DELETERIOUS arm (SASP-driven accumulation and tissue dysfunction); together they capture the antagonistic pleiotropy of senescence without requiring a single effect-reversing edge. Cancer entries may reference this module as the intrinsic barrier that oncogenic transformation must evade (e.g. oncogene-induced senescence in benign nevi).
4 nodes
0 cell types
4 processes
0 disorders
Used By
No disorder entries currently reference this module.
A corticotroph pituitary adenoma mechanism module in which activating USP8 alterations increase USP8 deubiquitinase activity, sustain EGFR signaling, increase POMC promoter activity, and drive corticotropin secretion. This module is intentionally separate from the somatotroph cAMP/PKA module because it explains corticotroph endocrine autonomy rather than GH-secreting somatotroph tumorigenesis.
4 nodes
1 cell type
4 processes
1 disorder
A pathway-agnostic convergent mechanism module for the premature fusion of a cranial suture (craniosynostosis, HP:0001363). Cranial vault sutures are intramembranous growth centres whose patency depends on a homeostatic balance: an undifferentiated suture mesenchymal stem-cell population (Gli1+/Axin2+) and anti-osteogenic transcriptional/boundary restraint (notably TWIST1 inhibition of RUNX2 and the TWIST1-EphA4 osteogenic boundary between the neural-crest frontal bone and the mesodermal parietal bone) hold the approaching bone fronts apart, while pro-osteogenic signalling (FGFR-MAPK, BMP) drives ossification. Premature fusion is the shared endpoint reached by either of two routes: (1) EXCESS pro-osteogenic drive (constitutive FGFR-MAPK signalling; loss of SMAD6/noggin restraint on BMP), or (2) LOSS of the anti-osteogenic boundary and stem-cell niche that normally keeps the suture patent (TWIST1 haploinsufficiency, suture MSC depletion). Both routes converge on net excess osteoblast differentiation in suture mesenchyme, premature bony bridging, and distortion of cranial growth.
3 nodes
3 cell types
3 processes
2 disorders
A conserved mechanism module for the hallmark of aging (Lopez-Otin et al.) termed deregulated nutrient sensing: the age-associated shift of the nutrient- and growth-sensing network toward persistent anabolic signaling. In a state of nutrient/growth-factor surplus, the anabolic sensors - the somatotroph GH/IGF-1 axis and the mechanistic target of rapamycin complex 1 (mTORC1), which senses amino-acid and nutrient abundance - are chronically engaged, while the catabolic, low-energy sensors (AMP-activated protein kinase, AMPK, and the NAD+-dependent sirtuins) are relatively attenuated. mTORC1 hyperactivation biases the cell toward growth and biosynthesis and suppresses macroautophagy, so the age-associated accumulation of damaged proteins and organelles is no longer efficiently cleared; the net result is accelerated cellular aging and age-related tissue decline. This is the conserved node that dietary restriction and the geroprotector drugs (rapamycin, metformin) act upon: down-shifting anabolic nutrient signaling extends lifespan and healthspan across model organisms. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the tissue- or disease-specific driver (e.g. constitutive mTORC1 activation from PI3K-AKT-TSC pathway lesions, or an accelerated-aging progeroid context) while preserving the conserved anabolic-signaling -> autophagy-suppression -> tissue-decline chain.
5 nodes
0 cell types
7 processes
2 disorders
A conserved mechanism module for the emerging hallmark of cancer (Hanahan & Weinberg): the reprogramming of energy metabolism. Proliferating cancer cells reprogram their metabolism to support biosynthesis rather than maximally efficient ATP production. The conserved causal chain runs from oncogenic signaling (and loss of tumor suppressors such as p53) that drives constitutive nutrient uptake, through a shift toward aerobic glycolysis - the Warburg effect, in which cells ferment glucose to lactate even when oxygen is plentiful - to the diversion of glycolytic and TCA-cycle intermediates into biosynthetic pathways (nucleotides, amino acids, lipids, NADPH), producing the biomass needed for cell division. The reprogrammed metabolism also acidifies the microenvironment (lactate export) and alters metabolite-driven gene regulation. Individual disorder entries declare conformance via conforms_to, substituting tumor-type-specific drivers (e.g., MYC- and PI3K-AKT-driven glucose addiction; IDH1/2 mutations producing the oncometabolite 2-hydroxyglutarate; VHL/HIF-driven glycolysis). This module is metabolically downstream of sustaining_proliferative_signaling.
3 nodes
0 cell types
3 processes
3 disorders
A conserved mechanism module for the hallmark of aging (Lopez-Otin et al., 2023) termed disabled macroautophagy: the age-associated decline of the macroautophagy machinery and the loss of its cytoplasmic quality-control function. Macroautophagy is the lysosomal degradation pathway - mediated by the evolutionarily conserved autophagy-related (ATG) genes - that sequesters and recycles dysfunctional organelles, aggregated proteins, and intracellular microbes, playing a fundamental role in cellular, tissue, and organismal homeostasis. Autophagic potential falls in normal and pathological aging; when ATG-mediated capture and lysosomal clearance fail, damaged cytoplasmic constituents accumulate, contributing to neurodegenerative, inflammatory, and other age-related disease. Because autophagy induction (by dietary restriction or nutrient-signaling inactivation) counteracts age-associated damage, restoring autophagic competence is a target for healthy-aging intervention. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disease-specific autophagy lesion (e.g. an ATG-pathway or autophagy-adaptor mutation, or secondary autophagy suppression) while preserving the conserved machinery-decline -> failed-clearance -> accumulated-damage chain.
3 nodes
0 cell types
3 processes
4 disorders
A conserved oncology mechanism module for tumors with impaired homologous recombination repair (HRR) or FA/BRCA pathway function. HRR-deficient cells accumulate replication-associated DNA damage and become selectively vulnerable to PARP inhibition and platinum-induced DNA lesions. Therapeutic pressure can then select escape states, including POLQ-associated microhomology-mediated repair and BRCA reversion events that restore HRR. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, preserving the conserved causal chain while substituting tumor-specific initiating genes, biomarker states, therapies, and resistance mechanisms.
5 nodes
0 cell types
7 processes
3 disorders
A conserved treatment-toxicity module representing the T-cell-mediated immune pathway by which culprit drugs trigger severe cutaneous adverse reactions (SCARs), with Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) as the prototype. Unlike the cytotoxic (myelosuppression), metabolic (DILI), and transport-mediated (nephrotoxicity) toxicity modules, the insult here is immunological: a drug or its metabolite is presented in an HLA-restricted manner to drug-specific T cells, which expand and kill keratinocytes via cytotoxic mediators (granulysin, FasL, perforin/granzyme), producing epidermal necrolysis and detachment. The culprit drug varies (allopurinol, aromatic antiepileptics, sulfonamides, abacavir, NSAIDs) and HLA risk alleles gate susceptibility, but the downstream cascade converges. This is a "side effect as mechanism" module: a drug-toxicity entry can declare conformance rather than re-deriving the chain. Related SCAR presentations (DRESS, AGEP) share the T-cell-mediated logic but are not the evidence focus here.
5 nodes
3 cell types
5 processes
2 disorders
A conserved treatment-toxicity module representing the final common pathway by which hepatotoxic drugs injure and kill hepatocytes. The culprit agent and the proximal trigger vary — dose-dependent reactive-metabolite formation (the acetaminophen/NAPQI archetype), bile salt export pump (BSEP) inhibition and cholestatic stress, or idiosyncratic immune-mediated injury — but the downstream sequence repeatedly converges on mitochondrial dysfunction and oxidative stress, hepatocyte cell death (necrosis and apoptosis), sterile/immune inflammatory amplification, and clinically apparent liver injury that can progress to acute liver failure. This is a "side effect as mechanism" module: it captures the adverse-drug-reaction pathophysiology shared across many hepatotoxic drugs, so a drug-toxicity entry can declare conformance rather than re-deriving the chain.
5 nodes
3 cell types
5 processes
1 disorder
A conserved treatment-toxicity module representing the final common pathway by which nephrotoxic drugs injure the renal tubule and cause acute kidney injury. The culprit agent varies — cisplatin and other platinums, aminoglycosides, vancomycin, tenofovir, amphotericin B, iodinated contrast, NSAIDs — but because the kidney concentrates, transports, and excretes these compounds, the downstream sequence repeatedly converges on proximal tubular drug accumulation, oxidative and mitochondrial stress, tubular epithelial cell death (apoptosis and acute tubular necrosis), tubulointerstitial inflammation, and a fall in glomerular filtration rate. This is a "side effect as mechanism" module: it captures the adverse-drug-reaction pathophysiology shared across nephrotoxic drugs, so a drug-toxicity entry can declare conformance rather than re-deriving the chain. It models the dose-dependent acute-tubular-injury arm; crystal/cast obstruction and immune-mediated interstitial nephritis are distinct arms noted in the literature but not the focus here.
5 nodes
1 cell type
6 processes
1 disorder
A conserved developmental-signaling module for hypohidrotic ectodermal dysplasia (HED) and the related EDA-pathway ectodermal dysplasias. Ectodermal appendages — sweat glands, hair follicles, and teeth — are induced from the surface ectoderm by a single linear signaling cascade: the TNF-family ligand ectodysplasin A (EDA) binds its TNF-receptor-family receptor EDAR, which recruits the intracellular adaptor EDARADD, activating the canonical NF-kappaB pathway (through the IKK complex, whose regulatory subunit is NEMO/IKBKG) to drive the transcriptional program of ectodermal placode formation and appendage morphogenesis. Because the pathway is a linear cascade, a loss-of-function lesion at any tier — the EDA ligand (X-linked HED), the EDAR receptor, the EDARADD adaptor, or the NEMO/IKBKG IKK subunit (ectodermal dysplasia with immunodeficiency) — converges on the same failure of canonical NF-kappaB activation and produces the same triad of hypohidrosis (sweat-gland aplasia), hypotrichosis (hair defects), and hypodontia/anodontia (tooth defects). Conforming disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific pathway component while preserving the conserved signaling-failure -> placode-failure -> appendage-failure chain.
3 nodes
3 cell types
5 processes
4 disorders
A conserved alveolar-destruction module representing the protease-antiprotease and oxidant-antioxidant imbalance paradigm that underlies pulmonary emphysema. Inhaled oxidants and particulates (chiefly cigarette smoke) or a genetic deficiency of alpha-1 antitrypsin trigger chronic lower-airway inflammation with recruitment of macrophages and neutrophils. The activated phagocytes release excess serine proteases (neutrophil elastase) and matrix metalloproteinases that overwhelm endogenous antiprotease defenses, producing proteolytic destruction of the alveolar-wall extracellular matrix, especially the elastic fiber network. Loss of elastin and collagen distends and ruptures alveolar walls, reducing elastic recoil and gas-exchange surface area. The acquired (smoking-related COPD) and inherited (alpha-1 antitrypsin deficiency) routes converge on this final common pathway, the permanent enlargement of distal airspaces with alveolar destruction that defines emphysema. Conforming disorder entries substitute the disorder-specific initiating insult (oxidant load versus antiprotease deficiency) while preserving the conserved causal chain.
5 nodes
2 cell types
6 processes
1 disorder
A conserved mechanism module for the fourth hallmark of cancer (Hanahan & Weinberg): the acquisition of unlimited replicative potential. Normal somatic cells can complete only a finite number of divisions because telomeres - the protective repeat caps on chromosome ends - shorten with each round of DNA replication, eventually triggering replicative senescence or crisis. This telomere clock is a powerful tumor-suppressive barrier. The conserved causal chain runs from progressive telomere attrition during clonal expansion through a proliferative crisis, to reactivation of a telomere-maintenance mechanism - in the great majority of cancers, transcriptional reactivation of the telomerase reverse transcriptase (TERT; via TERT promoter mutation, amplification, or rearrangement), and in a minority the recombination-based alternative lengthening of telomeres (ALT) - which stabilizes telomere length and confers unlimited proliferative capacity (replicative immortality). Individual disorder entries declare conformance via conforms_to, substituting the tumor-type-specific telomere-maintenance route (e.g., TERT promoter mutations in melanoma and glioblastoma, ALT in ATRX/DAXX-mutant tumors). This module is the immortality-enabling counterpart of the tumor-suppressive senescence captured in cellular_senescence and senescence_tumor_suppression.
4 nodes
0 cell types
4 processes
3 disorders
A conserved mechanism module for the hallmark of aging (Lopez-Otin et al.) termed epigenetic alterations: the progressive, partly stochastic remodeling of the epigenome with age. Aging is accompanied by drift in DNA-methylation patterns, chromatin reorganization, and altered histone modifications, which together perturb the epigenetic regulation of gene expression. The DNA-methylation changes are regular enough to build accurate multi-tissue "epigenetic clocks" that estimate biological age and reveal age acceleration in disease and cancer. Because these marks are, in principle, reversible, the epigenetic hallmark is a distinctive source of "druggable" targets against age-related decline - the basis of epigenetic-clock biomarkers and emerging epigenetic-reprogramming interventions. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disease-specific epigenetic lesion (e.g. a chromatin-modifier mutation, a methylation-clock acceleration, or an aging-associated transcriptional shift) while preserving the conserved drift -> altered-expression -> cellular-decline chain.
3 nodes
0 cell types
2 processes
1 disorder
A conserved network-hyperexcitability module representing the final common pathway of the epilepsies: a primary lesion in ion-channel function, synaptic transmission, or inhibitory circuitry shifts the balance of excitation and inhibition toward excitation, producing neuronal hyperexcitability and hypersynchronous firing that generate recurrent seizures. Genetic (channelopathy/synaptopathy), structural, metabolic, and acquired epilepsies differ in the upstream lesion but converge on excitation/inhibition (E/I) imbalance. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific lesion (e.g., SCN1A loss in Dravet syndrome, GABA-receptor variant, mTOR-pathway malformation) while preserving the conserved E/I-imbalance-to-seizure chain.
5 nodes
2 cell types
4 processes
11 disorders
A conserved cross-tissue pathophysiology module for the "epithelial barrier hypothesis" of allergic / type 2 inflammatory disease. Epithelial barriers of the skin, airway, gut, and esophagus share critical functions (a physical junctional barrier plus innate immune defense), and in allergic patients — regardless of tissue location — barrier homeostasis is skewed toward loss of terminal differentiation, reduced junctional integrity, and impaired innate defense. The conserved sequence is: an epithelial barrier insult or intrinsic junctional/differentiation defect disrupts the barrier; increased transepithelial allergen and microbial penetration activates innate immunity and antigen-presenting cells; a type 2 (TH2) milieu drives IgE class switch and allergic sensitization; and allergic disease is initiated at the affected barrier and, beyond it, along the atopic march (atopic dermatitis, food allergy, asthma, allergic rhinitis). Conforming disorder nodes substitute the tissue-specific epithelium and lesion (e.g., filaggrin/keratinocyte in atopic dermatitis; bronchial epithelium and tight-junction loss in asthma; squamous esophageal epithelium in eosinophilic esophagitis). This is the cross-tissue counterpart of the gut-specific `intestinal_barrier_dysfunction` module. Key conformance target: `epithelial_barrier_dysfunction#Increased Transepithelial Allergen Penetration and Innate Immune Activation`.
5 nodes
6 cell types
7 processes
4 disorders
A conserved pathological module representing hepatocellular endoplasmic reticulum (ER) storage disease: a mutant secretory protein misfolds during biogenesis, is retained and polymerized within the hepatocyte ER instead of being secreted, and imposes proteotoxic gain-of-function stress on the cell. Saturation of ER-associated degradation and autophagy drives chronic hepatocyte injury, and the resulting cycle of death and regeneration activates hepatic stellate cells, producing progressive fibrosis and cirrhosis. The conserved core is shared across ER storage hepatopathies, the prototype being Z alpha-1 antitrypsin (Z-AAT) polymer retention; mutant fibrinogen retention in hepatic fibrinogen storage disease (HFSD) follows the same cascade with a different stored protein. The terminal fibrotic step conforms to the conserved fibrotic response module.
4 nodes
3 cell types
6 processes
1 disorder
A conserved mechanism module for the second hallmark of cancer (Hanahan & Weinberg): the evasion of antiproliferative programs governed by tumor suppressors. Two master tumor-suppressor circuits enforce these programs: the retinoblastoma protein (RB) pathway, which integrates extracellular antigrowth signals to gate the G1/S transition, and the TP53 (p53) pathway, which senses intracellular stress (DNA damage, oncogene-induced hyperproliferation, hypoxia) and triggers cell-cycle arrest, senescence, or apoptosis. The conserved causal chain runs from inactivation of an RB- or p53-axis tumor suppressor (RB1/CDKN2A loss, cyclin D/CDK4-6 amplification, TP53 mutation, MDM2 amplification) through loss of cell-cycle-checkpoint and antiproliferative control, and additionally through loss of contact inhibition, to unrestrained proliferation. This is the antiproliferative-brake counterpart to sustaining_proliferative_signaling: that module models acquisition of growth-promoting drive, this one models loss of growth-restraining control. Individual disorder entries declare conformance via conforms_to, substituting the tumor-type-specific tumor-suppressor lesion (e.g., biallelic RB1 in retinoblastoma, germline TP53 in Li-Fraumeni, APC/Wnt in familial adenomatous polyposis, NF1 in neurofibromatosis).
4 nodes
0 cell types
5 processes
6 disorders
A conserved neurodevelopmental mechanism module for disorders caused by disruption of postsynaptic-density (PSD) scaffold and scaffold-regulatory proteins at glutamatergic (excitatory) synapses. Loss of a core PSD organizer reduces structural organization of the excitatory postsynaptic compartment, perturbs AMPA/NMDA glutamate-receptor localization and trafficking, and impairs activity-dependent synaptic plasticity. The shared path is an altered excitatory/inhibitory (E/I) balance and aberrant cortical or cortico-striatal circuit assembly that manifests as autism spectrum disorder, intellectual disability, and/or epilepsy. This module is intended as a narrow first prototype for NEUROCIPHER-style circuit pathomechanism modeling (dismech#3549); it is scoped to postsynaptic excitatory-scaffold genes such as SHANK3 (PSD scaffold) and SYNGAP1 (postsynaptic Ras-GAP that maintains PSD architecture and AMPA-receptor trafficking), with DLG4/PSD-95 as a further candidate. It intentionally excludes presynaptic active-zone genes, inhibitory-interneuron channelopathies (e.g. SCN1A), and neuronal subtype-specification/migration disorders, which belong in separate circuit modules.
5 nodes
1 cell type
6 processes
2 disorders
A conserved mechanism module for familial adult myoclonus epilepsy caused by intronic pentanucleotide repeat expansions that contain pathogenic TTTCA insertions. Across multiple unrelated host genes, the shared repeat architecture is linked to UUUCA repeat RNA toxicity, cerebellocortical dysfunction, and cortical hyperexcitability with myoclonus and seizures.
4 nodes
3 cell types
1 process
1 disorder
A conserved developmental mechanism module for the germline FGFR gain-of-function skeletal dysplasias and craniosynostosis syndromes. A recurrent activating mutation in a fibroblast growth factor receptor (most commonly FGFR3, less often FGFR2 or FGFR1) produces a constitutively active or ligand-hypersensitive receptor. The resulting sustained MAPK/ERK and STAT signaling acts in two skeletogenic compartments: in growth-plate chondrocytes it drives premature exit from proliferation and dysregulated chondrocyte differentiation, impairing endochondral ossification and producing chondrodysplasia; in cranial suture mesenchyme it accelerates osteoblast differentiation and matrix mineralization, producing premature suture fusion and craniosynostosis. The physiological CNP-NPR2 pathway antagonizes FGFR3-MAPK signaling and provides the therapeutic rationale for CNP-analog and FGFR-pathway antagonist therapy.
7 nodes
6 cell types
12 processes
11 disorders
The fungal cell-wall beta-1,3-glucan biosynthetic pathway and the point at which echinocandins interrupt it, structured as a causal cascade. The fungal cell wall is built largely of beta-1,3-glucan, a load-bearing polymer polymerized at the plasma membrane by the beta-1,3-glucan synthase complex whose catalytic subunit is encoded by FKS1 (and the paralog FKS2): the enzyme transfers glucose from UDP-glucose into a growing beta-1,3-glucan chain. The nascent glucan is then assembled into the wall, where it cross-links chitin and mannoproteins to form the intact, load-bearing fungal cell wall that resists internal turgor. This module traces that pathway as successive biological steps: beta-1,3-glucan synthesis at the membrane -> cell-wall assembly and integrity -> (when synthesis is blocked) cell-wall integrity failure and osmotic lysis. Echinocandins (caspofungin, micafungin, anidulafungin, and the long-acting rezafungin) are cyclic lipopeptides that act as non-competitive inhibitors of the glucan synthase catalytic subunit; depleting beta-1,3-glucan collapses wall integrity so that unopposed turgor drives osmotic lysis. Because mammalian cells have no cell wall and no homologous synthase, this is a fungal-specific, selectively toxic target that gives the echinocandin class the cleanest selectivity of any antifungal class. The pathway also generates the failure modes: acquired FKS1/FKS2 hotspot mutations reduce enzyme drug sensitivity (the cause of clinical breakthrough, especially in Candida glabrata), and whole pathogen lineages lie outside the class's reach — Cryptococcus species show negligible echinocandin activity and the Mucorales are intrinsically resistant — so organism identity alone can exclude the class before any susceptibility testing. This module defines the mechanism-of-action design pattern for echinocandin treatments: conforming fungal-disease entries link an echinocandin treatment to the specific node it inhibits via target_mechanisms.
5 nodes
0 cell types
4 processes
0 disorders
Used By
No disorder entries currently reference this module.
The fungal ergosterol biosynthesis pathway and the points at which the most widely used antifungal classes interrupt it, structured as a causal enzymatic cascade. Ergosterol is the fungal-specific membrane sterol, the functional analogue of cholesterol in mammalian cells; it maintains membrane fluidity, integrity, and the function of membrane-embedded proteins, and its biosynthesis is the most exploited antifungal target because the pathway is essential and fungal-specific. This module traces the pathway as successive biological steps: squalene is first epoxidised by squalene epoxidase (Erg1) — an early committed step and the target of the allylamines terbinafine and naftifine; the pathway then proceeds to lanosterol 14-alpha-demethylation by the cytochrome P450 Cyp51 (Erg11) — the target of the azoles (the triazoles fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole, and the topical imidazoles such as clotrimazole and miconazole), the antifungal workhorse class; ergosterol is then produced and incorporated into the fungal plasma membrane. Blocking either enzyme depletes ergosterol and causes accumulation of squalene or toxic methylated sterol intermediates, producing membrane dysfunction, growth inhibition, and (for terbinafine) fungicidal cell death — the antifungal consequence onto which both enzyme blocks converge. The module also encodes why azole therapy is failure-prone — point mutations in and overexpression of CYP51/ERG11, drug-efflux pumps (CDR/MDR), and the environmental Aspergillus fumigatus TR34/L98H allele select for azole resistance off the demethylase target. This module defines the mechanism-of-action design pattern for ergosterol-synthesis-targeting antifungal treatments: conforming fungal-disease entries link a treatment to the specific enzymatic step it inhibits via target_mechanisms.
5 nodes
0 cell types
5 processes
0 disorders
Used By
No disorder entries currently reference this module.
A conserved antifungal drug-mechanism module structured as a stepwise physical cascade: the polyene antifungals (amphotericin B, nystatin) act not on an enzyme but on the finished sterol of the fungal plasma membrane itself. The pathway begins with the ergosterol-enriched fungal plasma membrane, the eukaryotic counterpart of mammalian cholesterol that gives polyenes their selective target; amphiphilic polyene macrolactones then bind ergosterol with high affinity and extract it from the bilayer into large extramembranous "sterol sponge" aggregates while a minor membrane-inserted fraction forms ion-conducting pores; the resulting loss of membrane integrity drives potassium/ion efflux and oxidative injury; and the combined sterol depletion and permeabilization are fungicidal rather than merely fungistatic, precipitating cell lysis. Selectivity rests on a single fungal-specific feature — polyenes bind fungal ergosterol more avidly than mammalian cholesterol — but the discrimination is imperfect, which is why amphotericin B also extracts host cholesterol and causes dose-limiting nephrotoxicity, mitigated but not abolished by lipid (liposomal) formulations. Because the target is the membrane sterol rather than a mutable enzyme, clinically significant polyene resistance is rare; when it arises it is through reduced membrane ergosterol content (loss-of-function changes in the ERG ergosterol-biosynthesis pathway that substitute precursor sterols the drug binds poorly), which lowers the amount of drug-bindable target. This module defines the mechanism-of-action design pattern for polyene treatments: conforming fungal-disease entries link a treatment to the specific node it inhibits via target_mechanisms, the key conformance / treatment target being "Polyene Binding and Ergosterol Extraction / Pore Formation".
5 nodes
0 cell types
4 processes
0 disorders
Used By
No disorder entries currently reference this module.
The flucytosine (5-fluorocytosine, 5-FC) prodrug-activation pathway and the point at which this pyrimidine antimetabolite poisons fungal nucleic-acid metabolism. 5-FC has no intrinsic antifungal activity; it must be activated inside the fungus by a defined biochemical cascade, which this module traces as a causal sequence. First the drug is imported across the fungal membrane by the cytosine (purine-cytosine) permease Fcy2. Inside the cell, fungal cytosine deaminase Fcy1 deaminates 5-FC to 5-fluorouracil (5-FU) — the committed activation step and the structural basis of selectivity, because mammalian cells lack cytosine deaminase and therefore never activate the prodrug. Activated 5-FU is then anabolised, via the uracil phosphoribosyltransferase Fur1 and downstream kinases, to the fluorinated nucleotides 5-fluorouridine triphosphate (5-FUTP) and 5-fluorodeoxyuridine monophosphate (5-FdUMP). These effector nucleotides converge on two targets: 5-FUTP mis-incorporates into fungal RNA in place of uridylate, corrupting transcripts and inhibiting protein synthesis, while 5-FdUMP inhibits thymidylate synthase and blocks DNA synthesis. Because every step of this chain can be broken by a single loss-of-function mutation (FCY2 permease, FCY1 deaminase, or FUR1 phosphoribosyltransferase), monotherapy rapidly selects resistance, which is why flucytosine is given in combination — classically with amphotericin B for cryptococcal meningitis. The drug class acting on this pathway is the pyrimidine antimetabolite antifungals (flucytosine). This module defines the mechanism-of-action design pattern for flucytosine treatments: conforming fungal-disease entries link a treatment to the specific node it inhibits via target_mechanisms.
5 nodes
0 cell types
6 processes
0 disorders
Used By
No disorder entries currently reference this module.
A conserved mechanism module for the enabling characteristic of cancer (Hanahan & Weinberg): genome instability and mutation. Genome instability is the engine that generates the genetic diversity upon which selection acts during tumor evolution, accelerating acquisition of every hallmark capability. The conserved causal chain runs from an initiating insult that compromises genome integrity - inactivation of a "caretaker" genome-maintenance gene (mismatch repair, homologous recombination/BRCA, nucleotide-excision repair) and/or oncogene-induced DNA replication stress - through failure of DNA-damage surveillance and repair (frequently compounded by loss of the p53 and ATM/ATR checkpoint barriers), to an elevated mutation rate and chromosomal instability (the mutator phenotype). The resulting heritable diversity (point mutations, copy-number changes, aneuploidy, structural rearrangements) fuels clonal evolution and the stepwise acquisition of hallmark traits. Individual disorder entries declare conformance via conforms_to, substituting the tumor-type-specific caretaker lesion (e.g., MMR loss/microsatellite instability in Lynch syndrome, BRCA1/2 loss in HBOC, oncogene-induced replication stress in TP53/ATM-mutant sporadic cancers). The specific HRR/BRCA-deficiency therapeutic vulnerability is detailed in dna_repair_synthetic_lethality.
4 nodes
0 cell types
4 processes
6 disorders
A conserved mechanism module for the hallmark of aging (Lopez-Otin et al.) termed genomic instability, framed for the AGING process (distinct from the cancer-facing genome_instability_mutation module). Somatic cells are continuously exposed to endogenous and environmental sources of DNA damage - reactive oxygen species, replication errors, radiation, and mutagens - introducing tens of thousands of lesions per cell per day. A complex network of genome-maintenance systems removes this damage, but its capacity declines with age while damage continues to accrue; repair is sometimes erroneous and replication occasionally fails. The result is progressive accumulation of somatic mutations, epimutations, and persistent DNA damage across organs and tissues. Rather than (as in cancer) fueling a mutator phenotype and clonal selection, in the aging frame this damage load drives cellular dysfunction, senescence, and cell loss - a potentially unifying cause of the aging phenotype. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disease-specific genome-maintenance defect (e.g. the DNA-repair-deficiency segmental progeroid syndromes) while preserving the conserved damage -> failing-repair -> mutation-accumulation -> cellular-dysfunction chain.
4 nodes
0 cell types
2 processes
4 disorders
A conserved neurodegenerative module representing the final common pathway of glaucoma: impaired aqueous humor outflow raises intraocular pressure, which imposes mechanical and oxidative stress on the optic nerve head and drives progressive retinal ganglion cell apoptosis and optic nerve degeneration. Primary open-angle, angle-closure, exfoliation, and secondary glaucomas differ in the upstream cause of outflow obstruction but converge on this pressure-related retinal ganglion cell loss. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific outflow lesion (trabecular ECM accumulation, exfoliation material deposition, angle closure, neovascular membrane) while preserving the conserved IOP-to-neurodegeneration chain.
5 nodes
1 cell type
3 processes
2 disorders
A conserved neurodegeneration mechanism module representing excitotoxicity — the final common pathway in which excessive activation of glutamate receptors kills neurons. Diverse insults raise synaptic glutamate or mimic its action: impaired astrocytic glutamate clearance (e.g., EAAT2/GLT-1 loss in ALS), increased glutamatergic drive, or exogenous excitotoxins such as the cyanobacterial amino acid BMAA and methylmercury. Sustained overactivation of NMDA, AMPA, and kainate receptors causes pathological calcium influx and overload, which drives mitochondrial dysfunction and reactive-oxygen-species generation and ultimately excitotoxic neuronal death. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific source of glutamatergic overactivation and the selectively vulnerable neuronal population while preserving the conserved receptor-to-calcium-to-death chain.
4 nodes
3 cell types
5 processes
3 disorders
A conserved pathophysiology module representing the monosodium urate (MSU) crystal arthropathy pathway that produces gout. Sustained hyperuricaemia, arising from urate overproduction or, more commonly, renal and intestinal urate underexcretion mediated by urate transporters (URAT1, ABCG2), raises serum urate above its solubility limit. Supersaturation drives MSU crystal nucleation and deposition in joints and periarticular tissues; deposited crystals are phagocytosed by resident macrophages and engage the caspase-1-activating NLRP3 inflammasome, releasing bioactive interleukin-1 beta. IL-1 beta then drives acute neutrophil-rich inflammation, and recurrent crystal-driven flares progress to chronic tophaceous arthritis with erosive joint damage. Conforming disorder nodes substitute disorder-specific drivers of hyperuricaemia (enzymatic overproduction such as HPRT deficiency, or transporter-mediated underexcretion) while preserving the conserved crystal-deposition, inflammasome, and neutrophilic-inflammation chain.
5 nodes
2 cell types
5 processes
1 disorder
A conserved mechanism module for the hallmark of aging (Lopez-Otin et al., 2023) termed dysbiosis: the age-associated alteration of the gut microbiome and its downstream contribution to systemic aging. With age the composition of the intestinal microbiota drifts - older people show greater inter-individual variation and increasingly individual-unique communities - and this is coupled to increased intestinal permeability. Loss of barrier integrity permits microbial products to translocate, driving age-associated systemic inflammation and macrophage dysfunction; germ-free and cohort studies indicate the microbiota is causally involved in the age-related rise in circulating inflammatory mediators. Gut-microbiome patterns track healthy aging and even predict survival. Dysbiosis is thus an integrative hallmark feeding inflammaging and broader age-related morbidity. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disease-specific microbiome or barrier context while preserving the conserved microbiota-shift -> barrier-failure -> systemic-inflammation -> age-related-decline chain.
4 nodes
0 cell types
1 process
2 disorders
A conserved oncogenic mechanism module representing ligand-independent, constitutive activation of Hedgehog (Hh) signaling. Across Hedgehog-driven neoplasms, a genetic lesion removes the pathway's tonic restraint and locks the SMO-GLI axis in the "on" state: either loss-of-function of a negative regulator (the tumor suppressors PTCH1, PTCH2, or SUFU) or gain-of-function of the positive transducer SMO. Both gene-level directions converge on the same net effect - constitutive Smoothened activity and constitutive GLI transcriptional output - which drives Hedgehog-dependent proliferation and tumorigenesis. This module captures the shared causal chain and defines the mechanism-of-action pattern for SMO inhibitors (vismodegib, sonidegib): conforming disorder nodes declare conformance via conforms_to, and their SMO-inhibitor treatments link back through target_mechanisms to the "Constitutive Smoothened Activity" node they inhibit.
This is deliberately the GAIN-of-pathway-activity arm of Hedgehog biology. It is the mechanistic INVERSE of the developmental Hedgehog LOSS-of-function disorders (holoprosencephaly, GLI3-repressor syndromes, and the ciliary transduction failures), where reduced Hh signal output causes malformation rather than cancer. Those loss-of-signal disorders are modeled separately (see ciliopathy_dysfunction#Impaired Hedgehog Signal Transduction and limb_digit_patterning_serial_homology); this module intentionally does NOT fold the two opposite directions into one effect-reversing chain, mirroring the deliberate split between cellular_senescence and senescence_tumor_suppression.
4 nodes
0 cell types
4 processes
5 disorders
A conserved final-common-pathway module for the porphyrias — the inherited disorders of heme biosynthesis. Each porphyria results from a partial defect (or, for X-linked protoporphyria, a gain of function) at a different one of the eight enzymatic steps of the heme biosynthetic pathway (ALAD, HMBS, UROS, UROD, CPOX, PPOX, FECH; ALAS2). The enzymatic block impairs pathway flux and causes accumulation of the pathway intermediates immediately upstream of the lesion — the porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) and/or the porphyrins (uroporphyrin, coproporphyrin, protoporphyrin IX). The porphyrias split into two clinical arms that share this accumulation hub but diverge in the identity of the accumulating metabolite and its target tissue: (1) the acute hepatic porphyrias (ALAD porphyria, acute intermittent porphyria, hereditary coproporphyria, variegate porphyria), in which hepatic ALAS1 induction by porphyrogenic triggers (drugs, fasting, alcohol, hormonal cycling, infection) drives overproduction of the neurotoxic precursors ALA and PBG and precipitates acute neurovisceral attacks; and (2) the cutaneous and erythropoietic porphyrias (congenital erythropoietic porphyria, porphyria cutanea tarda, hepatoerythropoietic porphyria, erythropoietic protoporphyria, X-linked protoporphyria), in which photoreactive porphyrins accumulate and, on absorbing visible light, generate reactive oxygen species that injure skin and erythrocytes. Conforming disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific deficient enzyme, accumulating intermediate, and clinical arm while preserving the conserved block -> accumulation -> tissue-toxicity chain.
4 nodes
5 cell types
4 processes
3 disorders
A conserved pathophysiology module representing the premature destruction of circulating red blood cells that produces hemolytic anemia (HP:0001878, MONDO:0002280) across mechanistically diverse disorders. The initiating lesion varies: intrinsic membrane and cytoskeletal defects (e.g., hereditary spherocytosis), enzymopathies (e.g., glucose-6-phosphate dehydrogenase or pyruvate kinase deficiency), hemoglobinopathies (e.g., sickle cell disease, beta-thalassemia), and extrinsic antibody-mediated, complement-mediated, or mechanical (microangiopathic) insults. Despite this diversity, the downstream sequence repeatedly converges on reduced erythrocyte integrity, oxidative and membrane injury that marks cells for removal, accelerated extravascular splenic macrophage erythrophagocytosis and/or intravascular hemolysis, a shortened erythrocyte lifespan that outstrips compensatory erythropoiesis, and the resulting anemia with jaundice and splenomegaly. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting disorder-specific cell types and primary lesions (defective membrane protein, deficient enzyme, abnormal hemoglobin, or autoantibody) while preserving the conserved causal chain.
5 nodes
2 cell types
6 processes
4 disorders
A conserved hepatic pathophysiology module representing the final common pathway by which excess intrahepatocellular lipid drives progressive liver injury. When hepatocyte free fatty acid delivery and de novo lipogenesis exceed the capacity for fatty acid oxidation and very-low-density lipoprotein export, triglyceride and toxic non-triglyceride lipid species accumulate. These lipotoxic metabolites provoke endoplasmic reticulum stress, mitochondrial dysfunction, and oxidative stress, leading to hepatocyte injury and death with Kupffer-cell and macrophage-driven inflammation (steatohepatitis), hepatic stellate cell activation, and progressive fibrosis that can culminate in cirrhosis. The initiating context varies across metabolic-dysfunction-associated steatotic liver disease (MASLD/NAFLD), alcohol-associated steatohepatitis, and genetic forms (e.g., PNPLA3 and TM6SF2 variants), but the downstream lipid-overload-to-lipotoxicity chain is conserved. Conforming disorder nodes substitute the disorder-specific initiating insult while preserving the hepatocyte, Kupffer-cell, and hepatic stellate cell axis.
5 nodes
5 cell types
7 processes
1 disorder
The dependence of viruses on conserved host-cell factors, and the host-directed antiviral strategy that exploits it. Viruses are obligate intracellular parasites: every step of their life cycle co-opts host receptors, proteases, membranes, trafficking machinery, and metabolic pathways (host dependency factors). Because these factors are encoded by the comparatively stable host genome rather than the fast-mutating viral genome, drugs that target them offer two properties that direct-acting antivirals do not — broad-spectrum activity against multiple, unrelated viruses that share the same factor, and a higher genetic barrier to resistance. This module traces that logic as a causal cascade: a virus first depends on host factors to complete its life cycle; specific druggable host factors (the SARS-CoV-2 entry receptor ACE2 and the priming serine protease TMPRSS2 are the canonical example) are engaged; a host-directed agent blocks the host factor; the consequence is broad-spectrum suppression of replication; and an escape branch captures the two ways the strategy fails — the virus rewiring to an alternative host route (the Omicron shift away from TMPRSS2 toward endosomal, cathepsin-dependent entry) and on-target host toxicity, since the target is a host protein. Exemplar agents: the TMPRSS2 inhibitors camostat and nafamostat, soluble ACE2 receptor decoys, and host metabolic-pathway inhibitors. This is the host-side, broad-spectrum complement to the virus-targeted direct-acting modules (polymerase, protease, entry/fusion).
5 nodes
0 cell types
7 processes
2 disorders
A conserved endocrine module representing the final common pathway of hypothyroidism: a primary lesion in thyroid hormone production reduces circulating thyroid hormone, lifts the negative feedback restraint on TSH, diminishes thyroid hormone action at peripheral target tissues, and lowers basal metabolic rate, producing a generalized hypometabolic state. Autoimmune (Hashimoto), iodine-deficiency, dyshormonogenetic/genetic, iatrogenic, and drug-induced hypothyroidism differ in the upstream cause but converge on thyroid hormone deficiency. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific lesion (autoimmune follicular destruction, iodine deficiency, TPO/TG/NIS dyshormonogenesis, or central TSH/TRH deficiency) while preserving the conserved hormone-deficiency-to-hypometabolism chain.
5 nodes
1 cell type
4 processes
1 disorder
A conserved mechanism module representing the tumor-immune cycle that checkpoint inhibitors target. Across many cancer types, tumor cells generate neoantigens that provoke anti-tumor T cell responses, but adaptively upregulate immune checkpoint ligands (PD-L1, PD-L2) and recruit immunosuppressive cells to evade destruction. Immune checkpoint blockade (anti-PD-1, anti-PD-L1, anti-CTLA-4) reverses this evasion by restoring effector T cell function. This module captures the shared causal chain from neoantigen presentation through adaptive immune resistance to T cell exhaustion, and defines the mechanism-of-action pattern for checkpoint inhibitor treatments. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting tumor-type-specific details (driver mutations, neoantigen sources, tissue-specific immune microenvironment) while preserving the conserved immune evasion and checkpoint blockade response pattern.
4 nodes
2 cell types
5 processes
25 disorders
A conserved mechanism module for the intertwined hallmarks of aging (Lopez-Otin et al.) termed altered intercellular communication and chronic inflammation - together the phenomenon of "inflammaging": the chronic, low-grade, sterile systemic inflammation that develops with age in the absence of overt infection. Multiple age-associated stimuli converge to sustain it - the senescence-associated secretory phenotype (SASP), damage-associated molecular patterns from dysfunctional mitochondria, NLRP3 inflammasome activation, increased gut permeability and microbiota shifts, central obesity, immune dysregulation, and chronic infections. The resulting persistent cytokine milieu, propagated systemically through altered intercellular communication, is a highly significant risk factor for morbidity and mortality because most age-related diseases share an inflammatory pathogenesis. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disease-specific inflammatory driver and target tissue while preserving the conserved stimulus -> chronic-sterile-inflammation -> systemic-propagation -> age-related-morbidity chain.
4 nodes
0 cell types
3 processes
1 disorder
A conserved pathophysiology module representing the final common pathway of inherited rod-cone dystrophy / retinitis pigmentosa (HP:0000510, MONDO:0019200). Mutations in functionally diverse photoreceptor gene classes - phototransduction components (RHO, PDE6, CNG channels), ciliary and outer-segment structural proteins (RPGR, peripherin/RDS), RPE visual-cycle enzymes (RPE65, ABCA4), and pre-mRNA splicing factors - converge on a shared cascade. The primary lesion is expressed in or critically affects rod photoreceptors, producing metabolic and oxidative stress with protein mislocalization and misfolding, rod photoreceptor apoptosis, and non-cell- autonomous secondary cone degeneration with outer retinal thinning. The clinical consequence is progressive visual loss that begins as night blindness, advances to peripheral (then central) visual field constriction. Conforming disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific mutated gene and primary lesion while preserving the conserved rod-first, cone-second causal chain.
5 nodes
3 cell types
6 processes
11 disorders
The host innate antiviral pathway — from sensing of viral molecular patterns to the interferon-induced antiviral state — and the innate-immunity-modulator drug strategy that boosts it. Infected cells detect viral pathogen-associated molecular patterns (PAMPs), chiefly viral nucleic acid, through germline-encoded pattern-recognition receptors: the cytosolic RIG-I-like receptors (RIG-I, MDA5) for RNA, the cGAS-STING axis for DNA, and endosomal Toll-like receptors. Sensing drives induction of type I and type III interferons, which act in autocrine and paracrine fashion through the JAK-STAT pathway to transcribe hundreds of interferon-stimulated genes (ISGs); the ISG products establish an antiviral state that directly restricts viral replication. This module traces that cascade as causal steps — PAMP sensing -> interferon induction and JAK-STAT signaling -> ISG-mediated antiviral state -> restriction of viral replication — and adds the evasion branch every successful virus carries: dedicated viral antagonists (influenza NS1 is the prototype) that suppress interferon induction or signaling. Because the antiviral state is broad-spectrum and host-encoded, it is a drug target in its own right: innate-immunity modulators — recombinant or pegylated interferons (peginterferon lambda for COVID-19) and RIG-I/STING agonists — pharmacologically reinforce this pathway, the conceptual mirror of the viral-antagonism branch. Complements the host-dependency and direct-acting antiviral modules as the immune arm of broad-spectrum antiviral defense.
5 nodes
0 cell types
9 processes
6 disorders
Conserved cortical malformation and epilepsy mechanism in which disrupted ventral telencephalic or subpallial developmental programs impair GABAergic cortical interneuron specification, differentiation, or tangential migration from ganglionic eminence-derived progenitor domains into the developing cortex. The reusable skeleton is lineage-program disruption, interneuron progenitor differentiation failure and/or tangential migration failure, reduced or mislocalized cortical inhibitory interneurons, cortical excitation-inhibition imbalance, and developmental epilepsy or related neurodevelopmental impairment. ARX-related disease is the prototype; LIS1, DCX, tubulin, or other cortical malformation entries should conform only when interneuron defects are mechanistically central or explicitly documented.
5 nodes
4 cell types
6 processes
1 disorder
A conserved intestinal pathophysiology module representing convergent mechanisms that produce diarrhea through epithelial injury, junctional disruption, increased mucosal permeability, impaired absorption, and downstream fluid loss. The initiating insult varies across immune-mediated enteritides, treatment-related mucositis, dysbiosis-associated inflammation, and related disorders, but the downstream sequence repeatedly converges on barrier failure and diarrheal output.
7 nodes
3 cell types
4 processes
1 disorder
A conserved antibacterial lifestyle-gating module representing the intracellular niche occupied by obligate and facultative intracellular bacteria (e.g. Rickettsia, Bartonella, Brucella, Coxiella, Legionella, Chlamydia, Mycobacterium, intracellular phases of others). Unlike the cell-wall and protein-synthesis modules, the nodes here are not a single drug target but a pharmacokinetic gating principle: the pathogen resides inside host cells where hydrophilic, poorly cell-penetrant antibiotics — chiefly the beta-lactams — cannot accumulate, so they fail regardless of intrinsic susceptibility. Effective therapy requires agents that concentrate intracellularly: tetracyclines (doxycycline), macrolides, fluoroquinolones, and rifamycins. This module encodes WHY drug choice for intracellular infections departs from "any bactericidal antibiotic" and complements the target-based modules: a conforming disease may inhibit a ribosomal or cell-wall target, but only with a drug that first reaches the intracellular compartment.
2 nodes
0 cell types
2 processes
6 disorders
A conserved lens pathophysiology module representing the final common pathway by which heterogeneous insults converge on crystallin aggregation, light scattering, and loss of lens transparency. The initiating lesion varies across age-related (cumulative oxidation and post-translational modification), metabolic (diabetic and galactosemic polyol/osmotic and oxidative stress), and congenital/genetic (crystallin and other lens-protein gene defects) cataracts, but the downstream sequence repeatedly converges on loss of crystallin solubility and chaperone capacity, deposition of high-molecular-weight protein aggregates, increased light scatter, and visible lens opacity (Cataract, HP:0000518 / MONDO:0005129). Conforming disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific initiating insult (e.g., aldose reductase polyol flux in diabetic cataract, a CRYAA/CRYAB/CRYGD variant in congenital cataract, cumulative UV and oxidation in age-related cataract) while preserving the conserved crystallin-aggregation causal chain.
5 nodes
2 cell types
5 processes
0 disorders
Used By
No disorder entries currently reference this module.
A conserved developmental-patterning module that explains why a single patterning lesion produces a phenotype "bundle" repeated across serially homologous skeletal elements — most strikingly the autopod, where fingers and toes are patterned by the same molecular machinery and therefore tend to be malformed together. The anteroposterior axis of the limb is set by a gradient of GLI3 transcriptional repressor, generated by PKA-dependent processing of GLI3 and antagonized by long-range Sonic hedgehog (SHH) signaling from the posterior zone of polarizing activity; Indian hedgehog (IHH), the HOXD gene cluster, FGF8 from the apical ectodermal ridge, and WNT signaling provide the other patterning inputs that specify digit number, identity, and segment length. A dosage or activity change in any of these conserved signals perturbs digit-number and digit-identity specification, and because the homologous program operates in fore- and hindlimb autopods, the resulting malformation — polydactyly, syndactyly, brachydactyly, ectrodactyly, or triphalangism — characteristically appears in both hands and feet. Greig cephalopolysyndactyly and Pallister-Hall syndrome (GLI3 dosage), brachydactyly type A1 (IHH), and split-hand/foot malformation (HOXD/AER) differ in the upstream signal but converge on this serially homologous autopod phenotype. Conforming disorder entries declare conformance via conforms_to, substituting the disorder-specific patterning gene (GLI3, IHH, SHH/ZRS, HOXD13, TP63, WNT10B) while preserving the perturbed-patterning-to-serially-homologous-malformation chain.
3 nodes
1 cell type
4 processes
2 disorders
A conserved mechanism module for the hallmark of aging (Lopez-Otin et al.) termed loss of proteostasis: the age-associated decline of the protein homeostasis (proteostasis) network and the resulting accumulation of misfolded and aggregated proteins. In healthy cells a complex proteostasis network - molecular chaperones, the ubiquitin-proteasome system, and autophagy, with their regulators - coordinates protein synthesis, folding, conformational maintenance, and degradation. Chronic external and endogenous stresses erode this network's capacity during aging; as folding and clearance fail, non-native proteins misfold and aggregate. The aggregates (often beta-sheet-rich amyloid) accumulate, disproportionately burdening postmitotic cells such as neurons, driving proteotoxic dysfunction and the age-associated proteinopathies. This is the conserved core shared by the major neurodegenerative diseases. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disease-specific aggregating protein (e.g. amyloid-beta and tau in Alzheimer disease, alpha-synuclein in Parkinson disease, polyglutamine huntingtin in Huntington disease, TDP-43/SOD1 in ALS) while preserving the conserved network-decline -> misfolding -> aggregation -> proteotoxicity chain.
4 nodes
1 cell type
3 processes
3 disorders
A conserved pathological module representing the shared core of the lysosomal storage diseases (LSDs): an inherited deficiency of a specific lysosomal hydrolase (or of a non-enzymatic protein/transporter essential for normal lysosomal function) blocks catabolism of a macromolecular substrate, which then accumulates undegraded within the lysosome. Progressive intralysosomal storage distends the organelle and impairs lysosome function, triggering a secondary cascade of autophagic-flux block, disturbed signalling, mitochondrial and calcium dysregulation. The affected cell type — often only a subset of cells determined by where the substrate is normally turned over — undergoes storage-cell transformation, cytotoxicity, and (in the CNS) neuroinflammation and neurodegeneration, producing progressive multi-organ disease. This conserved core is shared across sphingolipidoses, mucopolysaccharidoses, glycoproteinoses, glycogenoses (Pompe), and free-substrate transport defects. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific deficient enzyme, stored substrate, and storage cell type while preserving the conserved deficiency -> accumulation -> lysosomal dysfunction -> cytotoxicity -> multisystem disease chain.
5 nodes
2 cell types
5 processes
43 disorders
A conserved mechanism module for inherited gametogenic failure caused by disruption of meiotic prophase I chromosome synapsis and recombination. In affected germ cells, programmed meiotic chromosome events fail at homolog pairing, synaptonemal complex assembly, homologous-recombination repair of DNA double-strand breaks, or pachytene checkpoint resolution. The shared path is meiotic arrest with germ-cell apoptosis, producing sex-dimorphic clinical outcomes: ovarian follicle depletion and primary ovarian insufficiency in 46,XX individuals, and spermatogenic arrest with non-obstructive azoospermia or Sertoli-cell-only syndrome in 46,XY individuals. This module is intended for meiotic genes such as SYCE1, MCM8, MCM9, STAG3, HFM1, MSH4, MSH5, DMC1, and SYCP3. It intentionally excludes upstream gonadal organogenesis and steroidogenic transcription-factor disorders such as NR5A1, WT1, SOX9, SRY, FOXL2, and DHH.
7 nodes
3 cell types
9 processes
7 disorders
A conserved final-common-pathway module for the "intoxication-type" inborn errors of intermediary metabolism: a deficient enzyme (or transporter) in amino-acid, organic-acid, fatty-acid, or urea-cycle metabolism causes accumulation of upstream toxic metabolites and/or a deficit in energy production. A catabolic stress (intercurrent illness, fasting, surgery, childbirth, or a protein load) unmasks the block and precipitates acute metabolic decompensation — the biochemical crisis of metabolic acidosis, hyperammonemia, and/or hypoglycemia. Toxic metabolites and bioenergetic failure then injure the brain, producing acute metabolic encephalopathy that can progress to irreversible neurological injury, multiorgan crisis, coma, or death. The urea-cycle disorders, classic organic acidemias (methylmalonic, propionic, isovaleric), maple syrup urine disease, and fatty-acid oxidation defects differ in the upstream enzymatic lesion and the identity of the accumulating metabolite but converge on this decompensation-to-encephalopathy chain. Conforming disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific deficient enzyme and toxic metabolite (e.g., OTC/ammonia in urea-cycle disorders, propionyl-CoA/methylmalonyl-CoA in organic acidemias, leucine/ketoacids in MSUD) while preserving the conserved chain.
5 nodes
3 cell types
6 processes
8 disorders
Conserved cortical malformation mechanism in which pathogenic variants in microtubule-associated proteins, tubulin subunits, gamma-tubulin nucleation machinery, dynein, or kinesin motors perturb microtubule dynamics and microtubule-based movement in developing neurons. The shared skeleton is microtubule apparatus perturbation followed by defective neuronal nucleokinesis/radial migration and cortical dyslamination or neuronal ectopia. This module is intended for lissencephaly, subcortical band heterotopia, and selected polymicrogyria-like malformations where microtubule-dependent neuronal migration is central.
4 nodes
3 cell types
7 processes
9 disorders
A conserved mechanism module for the hallmark of aging (Lopez-Otin et al.) termed mitochondrial dysfunction: the age-associated decline of mitochondrial quality and bioenergetic capacity and its downstream consequences. Because mitochondria convert dietary calories into ATP by oxidative phosphorylation while generating reactive oxygen species (ROS) as a by-product, and because mitochondrial DNA (mtDNA) is present in many copies and encodes essential respiratory-chain subunits, post-mitotic tissues accumulate somatic mtDNA mutations and respiratory-chain dysfunction with age. Declining bioenergetics and rising oxidative stress are incompletely counteracted because mitophagy (autophagic clearance of damaged mitochondria) also wanes, so dysfunctional, ROS-producing, pro-inflammatory mitochondria accumulate. Mitochondrial dysfunction feeds several other hallmarks - cellular senescence, chronic inflammation, and the decline in stem-cell activity - and converges on age-related tissue dysfunction. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disease-specific lesion (e.g. primary mtDNA/nuclear respiratory-chain defects in mitochondrial disease, or secondary mitochondrial injury in neurodegeneration and metabolic disease) while preserving the conserved damage -> bioenergetic-decline/ROS -> impaired-clearance -> tissue-decline chain.
5 nodes
0 cell types
5 processes
3 disorders
A conserved pathophysiology module representing post-infectious (and, more broadly, antigen-triggered) autoimmunity initiated by molecular mimicry. Across many disorders, an infectious or environmental antigen shares sequence or structural similarity with a host self-antigen; in a genetically susceptible individual (often HLA-restricted), this cross-reactive antigen activates autoreactive T and/or B lymphocytes that were not deleted by central tolerance. The resulting cross-reactive antibodies and effector T cells attack the mimicked self-tissue, and tissue damage releases additional self-antigens that prime further self-reactive clones (epitope spreading), converting a self-limited cross-reactive response into a self-sustaining, tissue-specific autoimmune disease. Conforming disorder nodes substitute the disorder-specific mimic pair (the pathogen/environmental epitope and the cross-reactive self-antigen) and the targeted tissue while preserving the conserved trigger -> cross-reactive lymphocyte activation -> effector tissue injury -> epitope spreading -> autoimmune disease chain.
5 nodes
2 cell types
7 processes
2 disorders
A conserved mechanism module for the mucopolysaccharidoses (MPS) that refines the generic lysosomal_substrate_accumulation trunk for the specific case of glycosaminoglycan (GAG) storage. A deficient GAG-degrading hydrolase or sulfatase leaves a specific GAG undegraded, and the chemical identity of that stored GAG — not the gene and not the clinical eponym — determines which tissues are affected and therefore which downstream pathological arm is engaged. The module is organized as a single GAG-accumulation hub that branches into three mechanistically distinct, independently reusable arms:
(1) a HEPARAN SULFATE-driven NEURONOPATHIC arm (undegraded heparan sulfate is a Toll-like-receptor-4 agonist that drives microglial neuroinflammation, secondary ganglioside accumulation and synaptic loss, and progressive central neurodegeneration);
(2) a DERMATAN SULFATE-driven SOMATIC / CONNECTIVE-TISSUE arm (storage in fibroblasts and extracellular matrix of bone, heart valve, cornea and viscera producing dysostosis multiplex, valvular disease, corneal clouding, organomegaly and airway infiltration); and
(3) a KERATAN SULFATE-driven SKELETAL-DYSPLASIA arm (storage in chondrocytes impairing endochondral ossification, producing skeletal dysplasia and mechanical craniovertebral instability WITHOUT primary neurodegeneration).
Each MPS biochemical type is generated by choosing the subset of arms that its stored-GAG profile switches on: MPS III (heparan sulfate only) engages the neuronopathic arm; MPS IV (keratan sulfate) engages the skeletal arm; MPS VI (dermatan sulfate only) engages the somatic arm; and MPS I, II and VII (dermatan + heparan sulfate) engage both the neuronopathic and somatic arms. Conforming disorder nodes substitute the disorder-specific deficient enzyme and stored GAG while preserving the arm structure.
8 nodes
4 cell types
4 processes
8 disorders
A conserved treatment-toxicity module representing the final common pathway by which cytotoxic insults to the bone marrow produce multilineage cytopenias and their clinical sequelae. The initiating insult varies — cytotoxic chemotherapy (fluoropyrimidines, platinums, topoisomerase inhibitors, alkylators), ionizing radiation, and other antiproliferative exposures — but the downstream sequence repeatedly converges on damage to proliferating hematopoietic stem and progenitor cells, suppression of marrow output, peripheral neutropenia/anemia/ thrombocytopenia, and the dose-limiting complications (infection, fatigue, bleeding) that follow. This is a "side effect as mechanism" module: it captures the conserved adverse-drug-reaction pathophysiology shared across many culprit drugs, so individual drug-toxicity entries (e.g. a chemotherapy-induced cytopenia entry) can declare conformance rather than re-deriving the chain.
4 nodes
5 cell types
4 processes
1 disorder
A conserved pathophysiology module representing the urinary stone-formation pathway that produces nephrolithiasis. An abnormal combination of metabolic derangements raises urinary supersaturation with respect to a lithogenic mineral: increased excretion of calcium (hypercalciuria), oxalate (hyperoxaluria), urate (hyperuricosuria) or cystine, low urine volume, or a pH derangement (alkaline urine for calcium phosphate, acidic urine for uric acid). Supersaturation thermodynamically drives crystal nucleation, growth and aggregation in the tubular lumen or on Randall's plaque. Crystals are retained by adhering to the apical surface of renal tubular epithelium rather than being harmlessly flushed out; retained crystal masses provoke epithelial injury and an NLRP3-inflammasome-driven inflammatory response that further promotes crystal attachment, and the stone enlarges into a symptomatic calculus causing obstruction, renal colic and recurrence. The module captures the shared core across idiopathic calcium oxalate, hypercalciuric, hyperoxaluric, cystinuric and uric acid stone disease. Conforming disorder nodes substitute the disorder-specific lithogenic solute and its handling defect (e.g., cystine transporter loss in cystinuria, AGT deficiency in primary hyperoxaluria, low urine pH in uric acid stones) while preserving the supersaturation -> nucleation -> retention -> injury -> stone causal chain.
5 nodes
2 cell types
4 processes
6 disorders
A conserved podocytopathy module representing the convergent glomerular filtration barrier failure that underlies nephrotic syndrome across primary and secondary causes. A podocyte insult — a circulating permeability factor, an immune or toxic mechanism, or an inherited slit-diaphragm/cytoskeleton gene defect (e.g., nephrin, podocin, actin-regulating proteins) — destabilizes the podocyte actin cytoskeleton, triggering foot process effacement and slit diaphragm disruption. Loss of this junctional architecture breaks the size- and charge-selective glomerular filtration barrier, producing massive proteinuria with progressive podocyte detachment, loss, and glomerulosclerosis. The convergent clinical consequence is nephrotic syndrome (nephrotic-range proteinuria, hypoalbuminemia, edema, and hyperlipidemia). Minimal change disease, focal segmental glomerulosclerosis, genetic NPHS1/NPHS2 podocyte-gene disorders, and secondary nephrotic syndromes all converge on this chain; conforming disorder nodes substitute the disorder-specific initiating lesion while preserving the conserved causal sequence.
5 nodes
1 cell type
4 processes
1 disorder
A conserved developmental module for Waardenburg-spectrum auditory-pigmentary disease. Diverse upstream lesions, including PAX3/SOX10/MITF transcriptional dysregulation and EDN3/EDNRB endothelin signaling deficiency, converge on impaired melanoblast migration, survival, or differentiation. This reduces melanocytes in skin, hair, iris, and the cochlear stria vascularis, producing pigmentary anomalies and sensorineural hearing impairment. Disorder entries reference these nodes via conforms_to and substitute the gene-specific trigger.
4 nodes
3 cell types
3 processes
2 disorders
Conserved cortical malformation mechanism in which centrosome, centriole, mitotic spindle, cell-cycle, or programmed-cell-death defects distort the neural progenitor pool during corticogenesis. The shared skeleton is progenitor centrosome/spindle or cell-number-control perturbation followed by abnormal radial-glial or neural-progenitor division, altered fate choice or apoptosis, progenitor-pool distortion, and abnormal cortical neuron output, cortical size, or gyration. This module is intended for microcephaly, microlissencephaly, simplified gyral pattern, pachygyria/PMG overlap, and selected infectious or chromosomal-deletion cortical malformations where progenitor biology is central.
6 nodes
4 cell types
14 processes
7 disorders
A conserved articular pathophysiology module representing the final common pathway of cartilage breakdown in osteoarthritis (HP:0002758, MONDO:0005178). Diverse initiating insults — abnormal mechanical overload or acute joint injury in primary/idiopathic and post-traumatic OA, and ECM or signaling variants in genetic OA — converge on chondrocyte stress, a catabolic/hypertrophic chondrocyte phenotype driven by proinflammatory cytokine signaling (IL-1beta, TNF), and upregulation of matrix-degrading enzymes (MMP-13, ADAMTS-5) that cleave type II collagen and aggrecan. Progressive matrix loss couples to subchondral bone remodeling, sclerosis, and osteophyte formation, producing joint cartilage degradation with pain and functional impairment. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting joint-specific or disorder-specific upstream lesions while preserving the conserved chondrocyte-to-matrix-degradation causal chain.
5 nodes
2 cell types
9 processes
2 disorders
A conserved metabolic bone-disease module representing the imbalance between osteoclastic bone resorption and osteoblastic bone formation that produces low bone mass and skeletal fragility. Across postmenopausal (estrogen-deficient), senile, glucocorticoid-induced, and genetic/secondary osteoporoses, the initiating lesion converges on the basic multicellular unit: tightly coupled remodeling becomes uncoupled, RANKL-driven osteoclastogenesis is enhanced relative to Wnt-driven osteoblast formation, and net negative bone balance with microarchitectural deterioration follows. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific upstream driver (estrogen withdrawal, glucocorticoid excess, Wnt-pathway or collagen gene defect) while preserving the conserved resorption/formation-imbalance chain.
5 nodes
3 cell types
5 processes
2 disorders
A conserved pancreatic pathophysiology module representing the final common pathway of pancreatitis, in which an acinar-cell insult triggers premature intracellular activation of trypsinogen to trypsin and a cascade of digestive proenzymes. Sustained pathological calcium signaling and defective autophagy amplify the injury, leading to acinar-cell autodigestion and necrosis with release of damage-associated molecular patterns (DAMPs), a local and systemic inflammatory response, and ultimately the clinical syndrome of pancreatitis with acute episodes and, on recurrence, chronic fibrosis and exocrine/endocrine insufficiency. Diverse etiologies (biliary obstruction, alcohol and its metabolites, hypertriglyceridemia, and hereditary PRSS1/SPINK1/CFTR variants) converge on this chain. Conforming disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific initiating insult (e.g., gallstone duct obstruction, alcohol metabolites, or a PRSS1 gain-of-function / SPINK1 inhibitor-loss variant) while preserving the conserved acinar autodigestion and inflammatory cascade.
5 nodes
3 cell types
8 processes
1 disorder
A conserved final-common-pathway module for parkinsonism (HP:0001300) — the movement-disorder phenotype (bradykinesia with rigidity and/or rest tremor) shared by Parkinson disease and a wide range of secondary, toxic, and genetic parkinsonian syndromes. Diverse upstream insults — genetic (SNCA, LRRK2, PRKN, PINK1) and environmental/toxic (MPTP, rotenone, paraquat, manganese) — converge on substantia nigra dopaminergic neurons, where mitochondrial complex I inhibition and oxidative stress, often with alpha-synuclein aggregation, drive nigrostriatal dopaminergic neurodegeneration. The resulting striatal dopamine deficiency unbalances the basal ganglia motor circuit and produces parkinsonism. This module is the dopaminergic-degeneration analogue of the disease-like-phenotype final-common-pathway modules: individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific upstream lesion (alpha-synuclein in PD, complex I inhibition by MPTP/rotenone, manganese deposition, LRRK2/GBA variants) while preserving the conserved nigrostriatal-to-parkinsonism chain.
5 nodes
2 cell types
6 processes
2 disorders
A conserved RNA-virus host-response module centered on NAD-dependent ADP-ribosylation. Viral infection and interferon signaling induce noncanonical PARPs that MARylate or PARylate host and viral proteins, restricting viral replication, shaping stress granules, and promoting innate cytokine responses. PARG and host macrodomains reset ADP-ribose marks, while viral macrodomains encoded by coronaviruses, alphaviruses, hepeviruses, and related RNA viruses erase ADP-ribose modifications to counter host antiviral defenses and support replication or pathogenesis.
5 nodes
0 cell types
8 processes
1 disorder
A conserved peripheral nerve degeneration module representing the final common pathway of peripheral neuropathy (HP:0009830 / MONDO:0005244). Metabolic, genetic, toxic/chemotherapeutic, and inflammatory insults to peripheral neurons and Schwann cells converge on impaired axonal transport, mitochondrial dysfunction, and oxidative stress in long axons, producing distal axonal degeneration and/or demyelination, length-dependent loss of sensory and motor nerve-fiber function, and ultimately the clinical phenotype of distal sensory loss, neuropathic pain, and weakness. Because long peripheral axons are most vulnerable to bioenergetic failure, the degeneration is characteristically length-dependent, producing a distal-to-proximal "glove and stocking" distribution that recurs across diabetic/metabolic neuropathy, inherited Charcot-Marie-Tooth disease, chemotherapy-induced peripheral neuropathy, and inflammatory/autoimmune neuropathy. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific initiating lesion (e.g., hyperglycemia/dyslipidemia in diabetic neuropathy; myelin/gap-junction gene mutations in CMT; microtubule- or mitochondria-targeting agents in chemotherapy-induced neuropathy; autoantibody/cell-mediated attack in inflammatory neuropathy) while preserving the conserved causal chain.
5 nodes
2 cell types
11 processes
4 disorders
A conserved craniofacial developmental-patterning module, the head counterpart of the limb/digit serial-homology module. The bone, cartilage, and connective tissue of the face derive from cranial neural crest cells that populate the serially repeated pharyngeal (branchial) arches; each arch is patterned by a reused molecular program — a dorsoventral EDN1-EDNRA-DLX5/6 code that assigns proximodistal/jaw identity, nested HOX information, and the neural-crest survival/proliferation machinery (ribosome and spliceosome biogenesis: TCOF1/POLR1, EFTUD2/SF3B4). Because the arches and their skeletal derivatives are serial homologs built by this shared program, a single lesion produces a recurrent malformation bundle across arch derivatives rather than an isolated defect: symmetric hypoplasia of the zygoma, maxilla, and mandible, ear anomalies, and palatal clefting travel together, and disruption of the EDN1-DLX code can even cause homeotic transformation of one arch element into another (mandibular toward maxillary identity). Treacher Collins syndrome (TCOF1/POLR1 ribosomopathy), the EFTUD2/SF3B4 mandibulofacial dysostoses, and auriculocondylar syndrome (EDN1-EDNRA-PLCB4-GNAI3 → DLX5/6) differ in the upstream lesion but converge on this neural-crest-to-arch-malformation chain. Conforming disorder entries declare conformance via conforms_to, substituting the disorder-specific lesion (ribosome/spliceosome biogenesis vs. EDN1-DLX arch-identity signaling vs. TFAP2A neurocristopathy).
3 nodes
4 cell types
4 processes
2 disorders
A conserved cortical-overgrowth module representing the shared pathomechanism of malformations of cortical development (MCDs) driven by constitutive activation of the phosphatidylinositol 3-kinase (PI3K)-AKT-mTOR growth pathway. Gain-of-function variants in PIK3CA, PIK3R2, AKT3, MTOR, or CCND2 - frequently arising as post-zygotic somatic (mosaic) events restricted to the developing brain - hyperactivate PI3K-AKT-mTOR signaling in neural progenitors. The resulting progenitor hyperproliferation and cell-cycle dysregulation drive cortical overgrowth (megalencephaly, hemimegalencephaly) together with impaired neuronal migration and dyslamination (polymicrogyria, focal cortical dysplasia), producing an epileptogenic cortical substrate and intractable seizures. The same pathway branch recurs across several disease entities and somatic-mosaic lesion types (hemimegalencephaly, focal cortical dysplasia type II, the megalencephaly- capillary malformation [MCAP] and megalencephaly-polymicrogyria-polydactyly- hydrocephalus [MPPH] spectrum, and the PIK3CA-related overgrowth spectrum such as CLOVES), so it is modeled as a module rather than a single disease entry. Conforming disorder nodes substitute the disorder-specific activating lesion (e.g., somatic PIK3CA in hemimegalencephaly/CLOVES, germline or postzygotic PIK3R2/AKT3 in the MCAP/MPPH spectrum, somatic MTOR in focal cortical dysplasia type II, CCND2 stabilization in MPPH) while preserving the conserved hyperactivation-to-overgrowth-to-epilepsy skeleton.
5 nodes
3 cell types
5 processes
0 disorders
Used By
No disorder entries currently reference this module.
A conserved malformation-of-cortical-development mechanism module in which defects in pial extracellular matrix anchoring, alpha-dystroglycan glycosylation and ligand binding, or GPR56-COL3A1 signaling destabilize the pial basement membrane and the basal endfeet of radial glial cells. The resulting pial boundary breach mispositions Cajal-Retzius cells and permits neurons or glial cells to overmigrate past the cortical surface, producing cobblestone-like cortical malformation and overlapping polymicrogyria-like phenotypes. This module captures a boundary-failure skeleton distinct from intrinsic neuronal migration arrest.
8 nodes
3 cell types
10 processes
2 disorders
A conserved neurodegeneration mechanism module for the autosomal dominant polyglutamine (polyQ) diseases caused by translated CAG trinucleotide repeat expansions. Across unrelated host genes, an elongated polyQ tract confers a dominant toxic gain of function on the disease protein: the mutant protein misfolds and aggregates (often forming neuronal intranuclear inclusions), sequesters transcriptional co-activators and disrupts gene expression, overwhelms ubiquitin-proteasome and autophagy clearance, and impairs mitochondrial bioenergetics. These convergent insults produce region-specific selective neuronal dysfunction and loss despite the disease protein being expressed widely. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the gene-specific initiating protein, the vulnerable neuronal population, and the affected brain region while preserving the shared causal chain.
6 nodes
3 cell types
9 processes
4 disorders
A conserved pulmonary vascular pathophysiology module representing the convergent mechanism by which heritable and idiopathic pulmonary arterial hypertension (PAH) and connective-tissue-disease-associated PAH produce sustained elevation of pulmonary arterial pressure. Pulmonary endothelial injury and dysfunction with impaired bone morphogenetic protein (BMP) signaling and an imbalance of vasodilators (nitric oxide, prostacyclin) versus vasoconstrictors (endothelin-1) triggers a pro-proliferative, anti-apoptotic switch in pulmonary artery smooth muscle cells. The resulting medial hypertrophy and intimal/plexiform lesions obstruct small pulmonary arteries, raising pulmonary vascular resistance and driving right ventricular pressure overload and failure. Although the initiating insult varies across heritable (BMPR2 mutation), idiopathic, and associated PAH, the downstream causal chain converges on this conserved remodeling sequence. Conforming disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting disorder-specific triggers and cell-type context while preserving the conserved chain.
5 nodes
2 cell types
7 processes
1 disorder
A conserved malformation-of-cortical-development mechanism module in which loss, hypomorphic receptor binding, or mislocalized expression of Reelin signaling perturbs the VLDLR/ApoER2-DAB1 pathway used by postmitotic cortical neurons. The shared skeleton is Cajal-Retzius Reelin cue or receptor-adaptor failure, impaired Dab1/Rap1/cadherin and cytoskeletal effector signaling, defective glia-independent terminal somal translocation, and abnormal inside-out cortical lamination with hippocampal and cerebellar organization branches. This module is intended for RELN/VLDLR/LRP8/DAB1-centered lamination mechanisms and for carefully bounded secondary Reelin misexpression branches, not for broad tubulinopathy or generic lissencephaly lumping.
8 nodes
3 cell types
11 processes
1 disorder
A conserved mechanism module for the third hallmark of cancer (Hanahan & Weinberg): resistance to programmed cell death. Apoptosis is a natural barrier to cancer that is engaged by the physiologic stresses of tumorigenesis, including oncogene-driven hyperproliferation and DNA damage. The mitochondrial (intrinsic) apoptotic program is governed by the BCL-2 family, in which pro-apoptotic effectors (BAX, BAK) and BH3-only sensitizers (BIM, BID, PUMA, NOXA, BAD) are opposed by pro-survival guardians (BCL-2, BCL-XL, MCL-1). The conserved causal chain runs from an apoptosis-evasion lesion (overexpression of pro-survival BCL-2 proteins, loss of pro-apoptotic effectors or of the p53-PUMA/NOXA axis) through a shifted BCL-2-family rheostat that blocks mitochondrial outer-membrane permeabilization and cytochrome c release, to impaired apoptotic execution and the survival of cells that should have died. Individual disorder entries declare conformance via conforms_to, substituting the tumor-type-specific apoptosis-evasion lesion (e.g., t(14;18) BCL2 overexpression in follicular lymphoma, MCL1 amplification, TP53 loss). The shifted rheostat is also the rationale for BH3-mimetic therapy (e.g., venetoclax), which can be captured with target_mechanisms on conforming treatments.
3 nodes
0 cell types
4 processes
1 disorder
A conserved oncology mechanism module for growth-factor and receptor tyrosine kinase (RTK) programs that signal through the GRB2 adaptor hub. Activated receptors create phosphotyrosine docking sites that recruit GRB2-containing complexes, coupling upstream RTK activity to RAS-MAPK and PI3K-AKT outputs that support proliferation, survival, and drug-adaptive fitness. The module also captures the emerging nuclear GRB2 function in RAD51-dependent replication-fork protection, linking the same adaptor control point to DNA damage response, PARP-inhibitor vulnerability, and innate immune activation when fork protection is lost.
5 nodes
0 cell types
9 processes
1 disorder
A conserved cochlear pathophysiology module representing the final common pathway to sensorineural hearing loss (HP:0000407; MONDO:0005365). Diverse initiating insults — hereditary defects of hair-cell stereocilia and mechanotransduction (e.g., MYO7A, stereociliary actin-core genes), defects of cochlear ionic homeostasis and gap-junction potassium recycling (GJB2/connexin 26), age-related (presbycusis), noise-induced, and ototoxic injury — converge on disruption of cochlear ionic homeostasis and oxidative stress, failure of hair-cell mechanotransduction, and apoptotic death of the non-regenerating mammalian cochlear hair cells. Hair-cell loss removes cochlear amplification and is followed by degeneration of spiral ganglion neurons, producing progressive, irreversible sensorineural hearing loss. Conforming disorder nodes substitute the disorder-specific primary lesion (stereocilia/MET gene defect, connexin/potassium-recycling defect, oxidative/metabolic insult, or ototoxic exposure) while preserving the conserved downstream chain.
5 nodes
2 cell types
6 processes
1 disorder
A conserved pituitary tumor mechanism module in which genetically distinct upstream alterations converge on increased cAMP availability and cAMP/PKA signaling in somatotroph-lineage cells. AIP loss, GPR101 dosage gain, and GNAS activating mutations enter the module through different molecular entry points but share the downstream pattern of increased cAMP/PKA signaling, growth hormone secretion, and somatotroph proliferation.
4 nodes
1 cell type
5 processes
3 disorders
A conserved mechanism module for the hallmark of aging (Lopez-Otin et al.) termed stem cell exhaustion: the age-associated decline in the number and function of tissue-specific stem cells, which erodes the regenerative capacity needed to maintain tissue homeostasis. Adult stem cells sustain tissue health by self-renewal and differentiation; with age, accumulated genetic mutations, epigenetic changes, and an altered extrinsic (niche/systemic) environment progressively impair stem-cell functionality. The resulting decline in self-renewal and regenerative output leaves tissues unable to replace lost or damaged cells, contributing to the functional decline of blood, muscle, brain, and other regenerative tissues. Stem cell exhaustion is an integrative hallmark - a downstream convergence of the primary damage hallmarks (genomic instability, telomere attrition, epigenetic alterations) acting on the stem compartment. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the tissue-specific stem population and driver (e.g. hematopoietic stem cell aging, satellite-cell decline, accelerated stem-cell aging in progeroid syndromes) while preserving the conserved damage -> functional-decline -> regenerative-failure chain.
3 nodes
2 cell types
2 processes
1 disorder
A conserved mechanism module for the first hallmark of cancer (Hanahan & Weinberg): the acquisition of growth-signal autonomy. Normal tissues tightly control the production and release of growth-promoting signals; cancer cells subvert this control to sustain chronic proliferation. The conserved causal chain runs from an oncogenic lesion that constitutively engages mitogenic signaling (activating receptor tyrosine kinase mutation/amplification, autocrine growth-factor loops, activating mutations in RAS/BRAF/PI3K, or loss of negative-feedback brakes such as PTEN/NF1) through constitutive RAS-MAPK and PI3K-AKT-mTOR signal output to growth-factor-independent cell-cycle entry and uncontrolled proliferation. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the tumor-type-specific driver (e.g., EGFR or ALK in NSCLC, BCR-ABL1 in CML, KIT/PDGFRA in GIST, activating BRAF V600E in melanoma) while preserving the conserved proliferative-signaling pattern. This is the proliferative counterpart to evading_growth_suppressors; together they capture the acquisition of autonomous proliferation plus loss of the antiproliferative brakes.
3 nodes
0 cell types
5 processes
8 disorders
A conserved presynaptic mechanism module representing the synaptic vesicle cycle — the trafficking cycle by which neurons load, dock, prime, fuse, and recycle synaptic vesicles to release neurotransmitter. Neurotransmitter release is mediated by Ca2+-triggered exocytosis of synaptic vesicles at the presynaptic active zone, followed by endocytosis and recycling that regenerates release-ready vesicles. Diverse monogenic lesions disrupt distinct steps of this shared cycle: docking/priming (Munc18-1/STXBP1, Munc13/UNC13A, RIM/RIMS1), Ca2+-triggered SNARE-mediated fusion (SNAP-25, syntaxin-1B, synaptobrevin-2/VAMP2, the Ca2+ sensor synaptotagmin-1, and complexin), and vesicle endocytosis/recycling (dynamin-1/DNM1, synaptojanin-1/SYNJ1, clathrin/AP-2). Because these proteins act in a single integrated release machine, their loss converges on reduced or dysregulated neurotransmitter release and impaired synaptic transmission, which manifests clinically as developmental and epileptic encephalopathy, presynaptic congenital myasthenic syndrome, and/or movement disorder. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific vesicle-cycle protein and vulnerable synapse population while preserving the conserved load-dock-prime-fuse-recycle chain.
5 nodes
1 cell type
7 processes
9 disorders
A conserved neurodegeneration mechanism module for the TDP-43 proteinopathies — the large family of disorders unified by pathological redistribution of the nuclear RNA-binding protein TDP-43 (encoded by TARDBP) into cytoplasmic, hyper-phosphorylated, ubiquitinated inclusions. Across unrelated primary etiologies, TDP-43 is depleted from the nucleus and aggregates in the cytoplasm, producing a coupled lesion: a nuclear loss-of-function arm that derepresses cryptic exons and corrupts RNA processing of disease-relevant transcripts (e.g., STMN2, UNC13A), and a cytoplasmic gain-of-function arm in which phosphorylated, ubiquitinated aggregates disturb proteostasis. These convergent insults produce region- and cell-type-specific selective neuronal dysfunction and loss despite TDP-43 being expressed ubiquitously. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disorder-specific upstream trigger (C9orf72 expansion, TARDBP/GRN mutation, repetitive head trauma, ageing) and the vulnerable neuronal population and brain region while preserving the shared TDP-43 causal chain.
4 nodes
2 cell types
5 processes
3 disorders
A conserved mechanism module for the hallmark of aging (Lopez-Otin et al.) termed telomere attrition: the progressive shortening of the protective telomere end-complexes of chromosomes with successive cell divisions and age. Because conventional DNA polymerases cannot fully replicate chromosome ends, telomeres shorten with each division unless maintained by telomerase; in most somatic tissues telomerase is limiting, so telomeres erode over the lifespan. Critically short or uncapped telomeres can no longer fulfil their protective function and are sensed as DNA double-strand breaks, triggering a persistent DNA-damage response that drives replicative senescence and blocks further division. The resulting failure to replenish tissues underlies telomere syndromes and contributes to age-related disease and mortality. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disease-specific lesion (e.g. telomerase-complex or shelterin mutations in the short-telomere/telomere-syndrome disorders) while preserving the conserved attrition -> DNA-damage/senescence -> tissue-failure chain.
3 nodes
0 cell types
3 processes
2 disorders
A conserved mechanism module for the fifth hallmark of cancer (Hanahan & Weinberg): the induction of angiogenesis. Tumors larger than ~1-2 mm outgrow the diffusion limit for oxygen and nutrients and must recruit new blood vessels to survive and grow. The conserved causal chain runs from intratumoral hypoxia and oncogenic signaling that stabilize hypoxia-inducible factor (HIF), through an "angiogenic switch" in which the balance of pro- and anti-angiogenic factors tips toward pro-angiogenic signals - chiefly VEGF-A acting on endothelial VEGFR2, with contributions from FGF, PDGF, and angiopoietins - to endothelial proliferation and sprouting that produce a structurally abnormal, leaky, tortuous tumor vasculature. This neovasculature sustains tumor growth and provides a route for metastatic dissemination, and is the target of anti-angiogenic therapy (anti-VEGF antibodies, VEGFR tyrosine kinase inhibitors). Individual disorder entries declare conformance via conforms_to, substituting tumor-type-specific drivers (e.g., VHL loss constitutively stabilizing HIF in clear cell renal cell carcinoma; VEGF-driven angiogenesis in glioblastoma). The anti-angiogenic drug-mechanism view can be captured with target_mechanisms on conforming treatments.
3 nodes
1 cell type
4 processes
3 disorders
A conserved mechanism module for the enabling characteristic of cancer (Hanahan & Weinberg): tumor-promoting inflammation. Chronic inflammation fosters multiple hallmark capabilities by supplying the tumor microenvironment with bioactive molecules. The conserved causal chain runs from an inflammatory stimulus (chronic infection, autoimmune or irritant-driven chronic inflammation, obesity-associated inflammation, or inflammation elicited by the incipient neoplasm itself) through recruitment and activation of innate and adaptive immune cells - tumor-associated macrophages, neutrophils, mast cells, and lymphocytes - that establish a pro-tumorigenic inflammatory microenvironment. These cells secrete growth factors, pro-angiogenic factors (VEGF), matrix-remodeling proteases (MMPs), reactive oxygen species that are themselves mutagenic, and cytokines (TNF, IL-6) that activate pro-survival/proliferative NF-kB and STAT3 signaling in tumor cells. The net effect is promotion of proliferation, survival, angiogenesis, invasion, and further genomic instability. Individual disorder entries declare conformance via conforms_to, substituting the tumor-type-specific inflammatory driver (e.g., Helicobacter pylori gastritis preceding gastric cancer, inflammatory bowel disease preceding colitis-associated colorectal cancer, viral hepatitis preceding hepatocellular carcinoma). This module complements immune_checkpoint_blockade, which models the adaptive immune-evasion arm.
3 nodes
2 cell types
3 processes
3 disorders
The late-stage virion-morphogenesis and egress pathway and the points at which assembly- and release-targeting antivirals interrupt it. Once a virus has replicated its genome and expressed its structural proteins, the infectious cycle is completed by a defined cascade: progeny virion components are assembled at a membrane assembly site; nascent particles bud out from the host plasma membrane; and, for influenza, the surface sialidase neuraminidase frees budded virions from cell-surface and viral sialic acid so they can disperse and spread. This module traces that cascade as a causal chain — assembly -> budding -> neuraminidase-mediated release -> suppression of spread — with an adaptive resistance branch. Two well-established antiviral drug classes act on it. In hepatitis C virus, the nonstructural phosphoprotein NS5A organises the membranous replication/assembly complex, and the NS5A inhibitors (the "-asvir" class — ledipasvir, velpatasvir, daclatasvir) disrupt replication-complex formation and virion assembly, acting at the earliest, assembly-organising step; they are essential components of curative direct-acting antiviral (DAA) combinations. In influenza, neuraminidase is a surface sialidase that cleaves terminal sialic acid residues to release budding progeny virions, and the neuraminidase inhibitors (oseltamivir, zanamivir, peramivir) are transition-state analogues that block this cleavage, trapping virions at the cell surface and arresting cell-to-cell spread — the canonical conformance and treatment target of the module. The net biological effect is suppression of progeny virion release and spread. Because the inhibitors act on defined target sites, target-site substitutions (influenza NA H275Y/R294K/I223R; HCV NS5A resistance-associated substitutions) escape them and gate drug choice. NOTE: influenza baloxavir is NOT an assembly/release inhibitor — it targets the PA cap-dependent endonuclease of the polymerase complex and belongs with the polymerase-complex mechanism, not here. See projects/ANTIVIRAL.md.
5 nodes
0 cell types
5 processes
0 disorders
Used By
No disorder entries currently reference this module.
The viral cell-entry pathway and the successive steps at which entry-targeting antivirals interrupt it. Every enveloped virus must cross the host plasma membrane to deliver its genome into the cytoplasm, and it does so through an ordered, virus-specific program built from surface glycoproteins and the host receptor/co-receptor/uptake factors they hijack. This module traces that program as a causal cascade: a virion first attaches to its primary receptor; for viruses that require one, a co-receptor is then engaged; the apposed viral and host membranes fuse to deliver the genome into the cytoplasm; productive entry is the biological output that entry inhibitors suppress. Three pharmacological strategies act on distinct steps of this cascade. Attachment inhibitors block receptor binding — fostemsavir clamps the HIV gp120 envelope so it cannot engage CD4, and the HBV/HDV peptide bulevirtide blocks docking of the large surface protein at the NTCP bile-acid transporter on hepatocytes. Co-receptor antagonists block the second step — the CCR5 antagonist maraviroc occupies CCR5 and works only against CCR5-tropic HIV. Fusion inhibitors block the committed third step — the gp41 fusion inhibitor enfuvirtide disrupts the six-helix-bundle conformational change that drives membrane merger. The membrane-fusion step is the committed, most-druggable point of no return for entry and is the canonical conformance/treatment target of the module, while attachment and co-receptor engagement are additional, upstream drug-target steps. The net biological effect of engaging any of these steps is suppression of productive viral entry before any cytoplasmic replication occurs. Because the targets are virus- and tropism-specific surface proteins rather than conserved enzymes, the same pathway generates the escape route: a tropism switch (CCR5-tropic to CXCR4-tropic HIV) or envelope-glycoprotein mutation abolishes inhibitor activity. Exemplar agents: fostemsavir and bulevirtide (attachment), maraviroc (co-receptor), enfuvirtide (fusion).
5 nodes
0 cell types
5 processes
0 disorders
Used By
No disorder entries currently reference this module.
The retroviral provirus-establishment pathway and the point at which integrase strand-transfer inhibitors (INSTIs) interrupt it, structured as a sequential biological cascade. Integration into the host genome is a step unique to the retroviruses, with no counterpart in non-retroviral antiviral targets. The pathway proceeds in obligate order: the virally encoded reverse transcriptase first copies the single-stranded viral RNA genome into a double-stranded linear cDNA; the virally encoded integrase then assembles with the cDNA ends into a nucleoprotein complex called the intasome and catalyzes 3'-processing followed by strand transfer, covalently inserting the viral cDNA into host chromatin; this establishes the stable integrated provirus that serves as the durable transcriptional template for progeny virus. The integrase strand-transfer reaction is the conserved, host-absent, retrovirus-specific catalytic step that the INSTI class exploits: raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir bind the intasome active site, chelate the two catalytic Mg2+ ions through an electronegative pharmacophore, displace the reactive 3' viral DNA end, and block strand transfer. The net biological effect is suppression of proviral integration — the reverse-transcribed cDNA is never inserted and persists only as short-lived unintegrated episomal forms, aborting establishment of permanent infection. Because integrase, like other antiretroviral targets, is subject to drug-pressure selection, the same step generates active-site resistance mutations (the Y143, Q148, and N155 pathways); the second-generation INSTIs dolutegravir and bictegravir, with a longer dissociative half-life and a high genetic barrier, retain potency against most single-mutant variants and anchor modern regimens.
5 nodes
0 cell types
5 processes
0 disorders
Used By
No disorder entries currently reference this module.
A conserved antiviral gating module representing the latent, integrated, or episomal viral genome that genome-replication-targeting antivirals cannot eradicate. Many medically important viruses do not exist solely as actively replicating particles: they archive their genome in a transcriptionally quiescent, drug-refractory form that persists for the lifetime of the host cell. The paradigms are the HIV integrated provirus in long-lived resting memory CD4+ T cells (the latent reservoir), herpes simplex virus latency in sensory neurons, and the hepatitis B covalently closed circular DNA (cccDNA) episome persisting in hepatocyte nuclei. Unlike the polymerase, protease, or entry modules, the nodes here are not a single drug target but a gating principle: direct-acting antivirals act on the replicating virus, so they suppress active replication and lower viral load but cannot clear a non-replicating archived genome. The therapeutic goal is therefore gated — lifelong suppressive therapy with viral rebound on interruption, and a reservoir-elimination / "functional cure" frontier — in sharp contrast to hepatitis C, which is curable because it neither integrates nor forms a stable nuclear reservoir. This module encodes WHY suppression is not cure for the latency-establishing viruses and complements the target-based antiviral modules: a conforming disease typically also conforms to a drug-target module (polymerase, protease, integrase) for the molecular mechanism of its suppressive agents, with this module explaining why that suppression must be indefinite.
3 nodes
0 cell types
3 processes
0 disorders
Used By
No disorder entries currently reference this module.
Conserved non-genetic cortical malformation mechanism in which prenatal neurotropic viral infection targets neural stem cells, neural progenitors, or radial glia during corticogenesis. The shared skeleton is fetal-brain viral exposure and progenitor infection followed by antiviral innate immune activation, mitotic or centrosome stress, apoptosis or cytopathy, depletion or premature differentiation of the progenitor pool, impaired neurogenesis, and congenital cortical malformation. Zika virus is the prototype evidence base, but conforming disease entries should substitute the virus-specific receptor, immune-evasion, placental, diagnostic, and systemic branches.
5 nodes
4 cell types
13 processes
1 disorder
A conserved mechanism module for virus-induced cancer (viral carcinogenesis), the enabling characteristic shared by the human tumor viruses. Roughly 10-15% of human cancers worldwide have a viral etiology. The conserved causal chain runs from persistent infection by an oncogenic virus, through deregulated expression of viral oncoproteins (frequently accompanied by incidental integration of viral DNA into the host genome), to inactivation of the core host tumor-suppressor axes (p53 and the RB/p16 cell-cycle brake) and hijacking of proliferative/survival signaling, producing genomic instability and deregulated proliferation that culminate in malignant transformation years to decades after the initial infection. Individual disorder entries declare conformance via conforms_to, substituting the virus-specific oncoprotein(s): high-risk HPV E6 (p53 degradation) and E7 (RB inactivation); EBV LMP1/EBNA; hepatitis B virus HBx; HTLV-1 Tax/HBZ; Merkel cell polyomavirus large T antigen (RB); and KSHV/HHV-8 LANA/vCyclin/vFLIP. This module captures the DIRECT viral-oncoprotein arm and is deliberately complementary to tumor_promoting_inflammation (the chronic-inflammation-to-cancer arm, e.g. viral hepatitis) and to the host-genetic hallmark modules (evading_growth_suppressors, genome_instability_mutation, enabling_replicative_immortality), which many viral cancers ALSO conform to.
5 nodes
1 cell type
5 processes
9 disorders
The viral genome-replication pathway and the point at which polymerase-targeting antivirals interrupt it. Every virus copies its genome with a virally encoded polymerase — an RNA-dependent RNA polymerase (RdRp) in most RNA viruses, a reverse transcriptase (RT) in retroviruses and hepadnaviruses, or a viral DNA polymerase in the large DNA viruses such as herpesviruses. This module traces that pathway as a causal cascade: replication is initiated when the polymerase engages the genome template; the catalytic core then selects and incorporates nucleotides one at a time; the nascent strand is elongated processively; and full-length progeny genomes are produced for packaging. The conserved catalytic incorporation step is the single most exploited antiviral drug target. Two pharmacological strategies act on it: nucleos(t)ide analogues — delivered as monophosphate prodrugs and activated by host kinases to their triphosphate form — are incorporated in place of the natural nucleotide and terminate the chain (immediately, or after a few residues for delayed terminators such as remdesivir), arresting elongation; non-nucleoside inhibitors bind an adjacent allosteric pocket and block catalysis without being incorporated. The net biological effect is suppression of genome replication and falling viral load. Because RdRps and RTs are error-prone, the same pathway generates the quasispecies from which active-site resistance mutations are selected. Exemplar agents: sofosbuvir (HCV NS5B), tenofovir/emtricitabine/lamivudine (HIV/HBV RT), remdesivir and molnupiravir (SARS-CoV-2 RdRp), aciclovir/ganciclovir/foscarnet (herpesvirus DNA polymerase).
5 nodes
0 cell types
4 processes
1 disorder
The viral polyprotein-maturation pathway and the point at which protease-targeting antivirals interrupt it. Many clinically important viruses translate their genome as one or more large polyprotein precursors that are themselves non-functional: their constituent structural proteins and replicative enzymes only become active after a virally encoded protease cleaves the precursor at defined junctions. This module traces that pathway as a causal cascade — the polyprotein precursor is first synthesized from the viral genome; the viral maturation protease then cleaves it into functional subunits; that cleavage drives the structural rearrangement of a nascent particle into a mature, infectious virion; and the antiviral endpoint, when the protease is blocked, is the release of immature, non-infectious particles. The conserved maturation protease is the single most exploited antiviral drug target after the polymerase, and the same druggable architecture recurs across unrelated families with different catalytic chemistries: the HIV-1 aspartyl protease (PR) cleaving the Gag and Gag-Pol polyproteins, the HCV NS3/4A serine protease processing the nonstructural polyprotein, and the SARS-CoV-2 main protease (Mpro / 3CLpro), a cysteine protease that liberates the replicase nonstructural proteins. Protease inhibitors — HIV PIs (atazanavir, darunavir, lopinavir), HCV NS3/4A "-previr" inhibitors (glecaprevir, grazoprevir), and SARS-CoV-2 nirmatrelvir — are substrate-mimetic or active-site-directed small molecules that occupy the protease cleft at the maturation-cleavage step, so virions are released immature and non-infectious. The key conformance / treatment target of this module is the proteolytic-maturation-cleavage node, "Proteolytic Maturation Cleavage by the Viral Protease". Because the protease active site tolerates resistance substitutions, and because several HIV and SARS-CoV-2 protease inhibitors are themselves cleared rapidly by host CYP3A, this drug class is characteristically boosted (ritonavir or cobicistat) and used in combination regimens — captured by the adaptive-escape branch off the cleavage node.
5 nodes
0 cell types
5 processes
0 disorders
Used By
No disorder entries currently reference this module.