{"gene":"TNFRSF12A","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":2003,"finding":"TWEAK binds to Fn14 (TNFRSF12A) with physiological affinity; Fn14 is the sole known receptor for TWEAK, and is a type I transmembrane protein that is the smallest member of the TNF receptor superfamily; TWEAK is a type II transmembrane protein that can also be shed as a smaller, biologically active soluble form.","method":"Receptor-ligand binding assays, cDNA transfection, recombinant protein characterization","journal":"Cytokine & growth factor reviews","confidence":"High","confidence_rationale":"Tier 2 — foundational receptor identification, replicated across multiple labs and cited >250 times","pmids":["12787562"],"is_preprint":false},{"year":2003,"finding":"Murine TWEAK binds to murine Fn14 transfectants and induces cell death; macrophages secrete functional soluble TWEAK; Fn14 overexpression confers sensitivity to TWEAK-induced cytotoxicity.","method":"cDNA transfection, monoclonal antibody generation, cell death assay, functional neutralization","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding and functional assay in transfected cells, single study","pmids":["12821115"],"is_preprint":false},{"year":2004,"finding":"TWEAK binding to Fn14 on human bronchial epithelial cells induces IL-8 and GM-CSF production through IκBα phosphorylation and NF-κB activation; anti-Fn14 blocking antibody abrogates this effect.","method":"Cell stimulation assay, blocking antibody, IκBα phosphorylation assay, NF-κB inhibitor (BAY11-7082)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological inhibition and blocking antibody confirm Fn14-dependent NF-κB pathway, single lab","pmids":["15120617"],"is_preprint":false},{"year":2005,"finding":"Intracerebroventricular injection of soluble Fn14-Fc decoy receptor after middle cerebral artery occlusion significantly reduces infarct volume, microglial activation, and apoptotic cell death in the ischemic penumbra, demonstrating TWEAK plays a pathogenic role in ischemia-induced brain injury.","method":"Murine MCAO model, intracerebroventricular injection of Fn14-Fc decoy receptor, histopathology, ELISA","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo loss-of-function with decoy receptor and defined phenotypic readout, single study","pmids":["15681834"],"is_preprint":false},{"year":2006,"finding":"TWEAK/Fn14 pathway inhibition (via soluble Fn14-Fc decoy receptor or genetic Fn14 deficiency) reduces blood-brain barrier permeability, NF-κB activation, MMP-9 activation, and basement membrane laminin degradation after cerebral ischemia, identifying Fn14 as a regulator of neurovascular unit integrity.","method":"Murine MCAO model, Fn14-Fc decoy receptor, Fn14 knockout mice, Evans blue dye extravasation, NF-κB/MMP-9 assays","journal":"Journal of cerebral blood flow and metabolism","confidence":"High","confidence_rationale":"Tier 2 — pharmacological and genetic loss-of-function, multiple orthogonal readouts, replicated findings","pmids":["16835630"],"is_preprint":false},{"year":2006,"finding":"TWEAK stimulation of mesangial cells expressing Fn14 induces NF-κB pathway activation (phosphorylated IκB) and dose-dependent chemokine secretion (CCL2, CCL5, CXCL10, CXCL1); Fn14-deficient mesangial cells and Fn14-knockout mice confirm Fn14 dependence of these proinflammatory effects.","method":"Cell stimulation, IκB phosphorylation assay, NF-κB inhibitor, Fn14-KO cells and mice, ELISA","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — pharmacological inhibition + genetic KO confirmation + in vivo validation, multiple orthogonal methods","pmids":["16424220"],"is_preprint":false},{"year":2006,"finding":"TWEAK, via Fn14, promotes proliferation and inhibits terminal differentiation of mesenchymal stem cells and primary mouse muscle myoblasts through NF-κB activation; Fn14-deficient myoblasts show reduced proliferative capacity and altered myotube formation; Fn14-KO mice display delayed skeletal muscle regeneration after cardiotoxin injury.","method":"In vitro myoblast culture, Fn14-KO mouse generation, NF-κB activation assay, cardiotoxin-injection regeneration model, histology","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple in vitro and in vivo phenotypes, >190 citations","pmids":["17124496"],"is_preprint":false},{"year":2006,"finding":"TWEAK/Fn14 interaction in osteoblastic MC3T3-E1 cells induces RANTES production via PI3K-Akt (not NF-κB), inhibits BMP-2-induced osteoblast differentiation via MAPK/Erk, and upregulates RANKL expression via MAPK/Erk; all effects abolished by Fn14-Fc chimera.","method":"Cell stimulation, pathway inhibitors, osteoblast differentiation markers, Fn14-Fc chimera neutralization","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 — multiple signaling pathways defined with pharmacological inhibitors and receptor-Fc neutralization, single lab","pmids":["16945157"],"is_preprint":false},{"year":2008,"finding":"TWEAK/Fn14 pathway deficiency (TWEAK-KO or Fn14-KO mice) or anti-TWEAK antibody reduces colitis severity, neutrophil/macrophage infiltration, chemokine/cytokine/MMP expression, and intestinal epithelial cell death after gamma-irradiation; Fn14 is expressed on colon epithelial cells and TWEAK induces epithelial production of inflammatory mediators, defining a TWEAK-intestinal epithelial cell axis.","method":"TNBS colitis model, TWEAK-KO and Fn14-KO mice, anti-TWEAK mAb, gene expression profiling, gamma-irradiation injury model","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic KO models, pharmacological blockade, and mechanistic in vitro studies, >60 citations","pmids":["19109961"],"is_preprint":false},{"year":2009,"finding":"Fn14-Fc fusion protein (TWEAK inhibitor) treatment in ApoE-/- mice reduces atherosclerotic plaque features; TWEAK/Fn14 signaling mediates lipid uptake in macrophages in vitro, implicating Fn14 in macrophage foam cell biology.","method":"ApoE-/- mouse model, Fn14-Fc treatment, plaque morphometry, in vitro macrophage lipid uptake assay","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo pharmacological blockade + in vitro mechanistic assay, single study","pmids":["19762780"],"is_preprint":false},{"year":2011,"finding":"Soluble TWEAK induces inflammatory cytokine secretion, MMP-9 production/activation, and expression of cell adhesion molecules in human cerebral microvascular endothelial cells (BBB model), and increases HCMEC monolayer permeability, demonstrating Fn14-mediated disruption of blood-brain barrier integrity.","method":"In vitro BBB model (HCMEC cultures), TWEAK stimulation, cytokine ELISA, MMP assay, permeability assay","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 3 — in vitro BBB model with multiple functional readouts, single lab","pmids":["23320797"],"is_preprint":false},{"year":2011,"finding":"IL-13-induced intestinal epithelial cell apoptosis (caspase-3 activation) requires TWEAK, Fn14, and ADAM17-mediated endogenous TNF-α secretion; similarly, TNF-α-induced caspase activation requires IL-13, TWEAK, and Fn14, revealing a cooperative IL-13–TWEAK/Fn14–TNF-α axis in mucosal damage.","method":"Intestinal explant cultures from TWEAK-KO mice, caspase-3 activation assay, ADAM17 inhibition, gene expression profiling","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO, pharmacological inhibition, and multiple orthogonal mechanistic readouts in single study","pmids":["21893119"],"is_preprint":false},{"year":2011,"finding":"Anti-Fn14 agonistic antibody (BIIB036) activates Fn14 signaling, promotes tumor cell apoptosis, and inhibits tumor growth in vivo; increasing antibody valency enhances anti-tumor effect, suggesting higher-order Fn14 receptor cross-linking is required for full agonism; full Fc effector function is required for maximal in vivo activity.","method":"Fn14 signaling assay, in vitro apoptosis assay, multiple xenograft models, valency manipulation, Fc variant comparison","journal":"mAbs","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic antibody characterization with multiple in vitro and in vivo models, single lab","pmids":["21697654"],"is_preprint":false},{"year":2011,"finding":"Anti-Fn14 antibody (ITEM-4) conjugated to recombinant gelonin (ITEM4-rGel) specifically internalizes into Fn14-positive tumor cells within 2 hours, demonstrating that Fn14 undergoes receptor-mediated internalization; the immunoconjugate kills Fn14-expressing cells via apoptosis with HMGB1 release.","method":"Confocal microscopy internalization assay, cytotoxicity assay, apoptosis detection, xenograft tumor model","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — direct internalization imaging with functional cytotoxicity readout, single lab","pmids":["21586630"],"is_preprint":false},{"year":2012,"finding":"TWEAK/Fn14 axis promotes cardiac fibroblast proliferation and collagen synthesis via NF-κB pathway activation and subsequent MMP-9 upregulation; siRNA silencing of Fn14 inhibits TWEAK-induced NF-κB activation, proliferation, and collagen synthesis.","method":"Neonatal rat cardiac fibroblast culture, siRNA knockdown of Fn14, NF-κB activation assay, MMP-9 measurement, collagen synthesis assay","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA knockdown with multiple mechanistic readouts, single lab","pmids":["22555979"],"is_preprint":false},{"year":2013,"finding":"Fn14 undergoes TWEAK-independent self-association into dimers mediated by an 18-amino acid region within its cytoplasmic domain; an intermolecular disulfide bond at cysteine residue 122 mediates Fn14 dimerization; a TWEAK-binding-deficient Fn14 deletion mutant can still activate the NF-κB pathway in transfected cells, demonstrating TWEAK-independent Fn14 signaling.","method":"Deletion mutagenesis, co-immunoprecipitation, SDS-PAGE under non-reducing conditions, NF-κB reporter assay, transfection","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis combined with biochemical reconstitution of dimerization and functional NF-κB assay in single study","pmids":["23750247"],"is_preprint":false},{"year":2013,"finding":"Anti-Fn14 antibodies (PDL192 and P4A8) selectively activate the alternative (non-canonical) NF-κB pathway but not classical NF-κB, IL-8 production, or cell death; oligomerization or FcγR-binding converts these antibodies into full Fn14 agonists mimicking membrane TWEAK; soluble TWEAK predominantly triggers alternative NF-κB and enhances TNF-induced cell death, while membrane TWEAK activates all Fn14-associated pathways, demonstrating valency-dependent differential Fn14 signaling.","method":"NFκB pathway analysis (p100 processing, classical NF-κB), IL-8 ELISA, cell death assay, protein G oligomerization, FcγR-binding, soluble vs. membrane TWEAK comparison","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal signaling readouts comparing different ligand forms and antibody valencies, mechanistically rigorous","pmids":["23532848"],"is_preprint":false},{"year":2013,"finding":"Fn14 activation in cardiac fibroblasts induces collagen expression via RhoA-dependent nuclear translocation of myocardin-related transcription factor-A (MRTF-A)/MAL; Fn14-deficient mice show substantially reduced RV fibrosis and dysfunction after pulmonary artery banding; Fn14 expression in cardiac fibroblasts is regulated by endothelin-1.","method":"Fn14-KO mice (PAB model), cell culture RhoA/MRTF-A pathway analysis, fibroblast proliferation/differentiation assay, endothelin-1 treatment","journal":"Basic research in cardiology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO in vivo + mechanistic pathway identification in vitro, multiple orthogonal methods","pmids":["23325387"],"is_preprint":false},{"year":2013,"finding":"TWEAK reduces PGC-1α levels and mitochondrial content (~50%) in skeletal muscle; PGC-1α overexpression inhibits TWEAK-induced NF-κB activation (~50%) and dramatically reduces atrogene (MAFbx/MuRF1) expression (~90%); PGC-1α overexpression also prevents inducible Fn14 expression in denervated muscle, demonstrating a regulatory circuit between TWEAK-Fn14 signaling and PGC-1α in muscle atrophy.","method":"TWEAK-Tg mice, Fn14-KO mice, TWEAK-KO mice, PGC-1α transgenic mice, denervation model, NF-κB activity assay, gene expression analysis","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic mouse models with mechanistic NF-κB and atrogene pathway readouts, multiple orthogonal approaches","pmids":["24327607"],"is_preprint":false},{"year":2013,"finding":"TWEAK/Fn14 pathway activation in chronic colitis promotes Th2-type immunity and fibrosis through upregulation of TSLP in colon epithelial cells; IL-13 potentiates TWEAK-induced TSLP production; TWEAK and IL-13 synergistically promote fibroblast proliferation; Fn14-KO mice show reduced inflammation, fibrosis, and TSLP in chronic colitis model.","method":"Fn14-KO mice (chronic colitis model), TSLP receptor-KO mice, colon explant TSLP assay, fibroblast proliferation assay","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic KO models + mechanistic in vitro assays defining IL-13–TWEAK–TSLP axis","pmids":["23462911"],"is_preprint":false},{"year":2013,"finding":"Fn14 is expressed in podocytes and is upregulated by inflammatory cytokines; TWEAK activates NF-κB in cultured podocytes and increases MCP-1 production via NFκB (blocked by parthenolide); Fn14-KO mice with protein overload proteinuria show reduced glomerular macrophage infiltration and MCP-1 levels.","method":"Podocyte cell culture, NFκB inhibitor, Fn14-KO mice (protein overload proteinuria model), adenovirus-mediated TWEAK overexpression in mice, macrophage infiltration assay","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 — pharmacological inhibition + in vivo genetic and viral gain/loss-of-function approaches","pmids":["23999007"],"is_preprint":false},{"year":2014,"finding":"TWEAK/Fn14 signaling activates canonical NF-κB pathway to promote myoblast proliferation and inhibit myogenesis, while also activating non-canonical NF-κB to promote myoblast fusion; both pathways are regulated by cIAP1, which is an essential downstream signaling component of Fn14.","method":"NF-κB pathway analysis (canonical vs. non-canonical), cIAP1 characterization, myoblast proliferation/differentiation/fusion assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — pathway dissection with canonical vs. non-canonical NF-κB readouts, review with synthesis of multiple mechanistic studies","pmids":["24550918"],"is_preprint":false},{"year":2014,"finding":"FN14 promotes prostate cancer bone metastasis through IKKβ-dependent NF-κB signaling; FN14 expression is inversely correlated with androgen receptor (AR) signaling output; AR binding to the FN14 enhancer decreases FN14 expression, defining an upstream regulatory mechanism.","method":"In vivo bone metastasis model with FN14 depletion, FN14 reconstitution with IKKβ, AR ChIP (AR binding to FN14 enhancer), NF-κB signaling assay, clinical sample correlation","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo functional reconstitution and ChIP demonstrating AR regulation of Fn14, single lab","pmids":["24970477"],"is_preprint":false},{"year":2014,"finding":"Large-magnitude (12%) cyclic mechanical stretch activates Ca2+ influx → ROS generation → ASK1-JNK pathway → transient Fn14 upregulation in MC3T3-E1 osteoblasts; cells with elevated Fn14 then acquire sensitivity to TWEAK-induced apoptosis; small-magnitude stretch (1%) activates ERK promoting osteogenic gene expression without Fn14 upregulation.","method":"Cyclic stretch assay, ROS measurement, kinase pathway inhibitors, JNK/p38/ERK activation assays, Fn14 expression measurement, apoptosis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway dissection with pharmacological inhibitors and functional outcome, single lab","pmids":["24446436"],"is_preprint":false},{"year":2014,"finding":"TWEAK/Fn14 axis mediates skeletal muscle atrophy by activating NF-κB signaling and upregulating ubiquitin-proteasome system, autophagy, and caspase-mediated proteolysis; TWEAK also causes slow-to-fast fiber type transition and represses mitochondrial content and oxidative phosphorylation capacity.","method":"In vitro myotube atrophy assay, NF-κB activation, proteasome assay, autophagy markers, fiber-type analysis, mitochondrial content measurement; TWEAK-Tg and Fn14-KO mouse models","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple in vitro and in vivo genetic models with diverse mechanistic readouts, extensively replicated","pmids":["24478779"],"is_preprint":false},{"year":2014,"finding":"FGFR-1 and Fn14 physically interact (co-immunoprecipitation and proximity ligation assay) in cardiomyocytes; FGF1-induced cardiomyocyte cell cycle reentry is blocked by Fn14 inhibition, and TWEAK-induced cell cycle activation is blocked by FGFR-1 inhibition; FGF1 and TWEAK act synergistically via PI3K/Akt signaling to induce cell cycle reentry; the FGFR-1/Fn14 interaction is enhanced in the presence of both ligands.","method":"Co-immunoprecipitation, proximity ligation assay, kinase inhibitors, Fn14 overexpression, cell cycle reentry assay in neonatal and adult cardiomyocytes, PI3K/Akt inhibition","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1-2 — direct protein-protein interaction by two independent methods + functional mutagenesis/inhibition + mechanistic PI3K/Akt pathway","pmids":["24571920"],"is_preprint":false},{"year":2014,"finding":"TWEAK/Fn14 signaling promotes NSCLC cell survival via NF-κB-dependent upregulation of Mcl-1; TWEAK-induced chemo- and radioresistance is Mcl-1-dependent; Mcl-1 inhibition (EU-5148) or siRNA depletion sensitizes TWEAK-treated NSCLC cells to cisplatin or radiation; Bcl-2/Bcl-xL inhibition had minimal effect.","method":"TWEAK stimulation, NF-κB activation assay, Mcl-1 siRNA, pharmacological Mcl-1 inhibitor (EU-5148), cisplatin/radiation survival assay","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA and pharmacological inhibition with multiple functional readouts, single lab","pmids":["24469836"],"is_preprint":false},{"year":2014,"finding":"Fn14 genetic deletion reduces muscle pathology and improves function in a mouse model of RNA toxicity (DM1); anti-TWEAK antibody treatment similarly improves muscle histopathology and function; Fn14 induction in DM1 is associated with downstream NF-κB pathway activation.","method":"Fn14-KO mice in RNA toxicity model, anti-TWEAK antibody treatment, NF-κB signaling assay, muscle histopathology, functional outcome measures","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO and pharmacological blockade with mechanistic NF-κB pathway assay, single study","pmids":["25504044"],"is_preprint":false},{"year":2014,"finding":"Fn14 levels are increased in aged (18-month) mouse skeletal muscle; Fn14-KO blunts age-associated fiber atrophy and reduces NF-κB activity, ubiquitinated protein levels, autophagy-related Atg12 expression, inflammatory gene expression, and interstitial fibrosis in aged muscle.","method":"Fn14-KO mice (aging model), NF-κB DNA-binding assay, ubiquitin/autophagy markers, fiber morphometry, histology","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with multiple molecular and histological readouts, single study","pmids":["24680686"],"is_preprint":false},{"year":2014,"finding":"TWEAK/Fn14 pathway is activated after resistance exercise in human skeletal muscle; Fn14 gene and protein expression peaks at 8–12 h post-resistance exercise; downstream markers indicate signaling through the alternative (non-canonical) NF-κB pathway; running exercise induces Fn14 to a much lesser extent, indicating exercise mode dependency.","method":"Human skeletal muscle biopsies, gene and protein expression time course, alternative NF-κB pathway markers","journal":"Journal of applied physiology","confidence":"Medium","confidence_rationale":"Tier 2 — human in vivo temporal expression with pathway markers, single study","pmids":["25539934"],"is_preprint":false},{"year":2015,"finding":"Fn14 expressed in tumors (not host) causes cancer-induced cachexia; tumors in Fn14- and TWEAK-deficient hosts develop comparable cachexia to wild-type, while anti-Fn14 antibodies prevent tumor-induced inflammation, fat and muscle mass loss, and dramatically extend lifespan.","method":"Fn14-KO and TWEAK-KO host mice, anti-Fn14 antibodies, tumor implantation models, body composition analysis, survival studies","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological dissection of tumor vs. host Fn14, multiple orthogonal approaches, high-impact journal","pmids":["26359988"],"is_preprint":false},{"year":2015,"finding":"TGF-β signaling increases Fn14 expression through SMAD4 binding to the Fn14 promoter; Fn14 siRNA blocks extracellular matrix gene expression and fibroblast activation even in the presence of TGF-β1; Fn14 overexpression increases ECM gene expression, positioning Fn14 as a TGF-β/SMAD4 transcriptional target that drives fibroblast activation.","method":"SMAD4 ChIP on Fn14 promoter, Fn14 siRNA, Fn14 overexpression, ECM/collagen gene expression assay in dermal fibroblasts","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1-2 — ChIP demonstrating SMAD4 binding to Fn14 promoter, combined with functional siRNA and overexpression studies","pmids":["26625141"],"is_preprint":false},{"year":2016,"finding":"Fn14 plays a protective role during acute intestinal inflammation; Fn14-/- mice have enhanced susceptibility to DSS colitis and develop colonic tumors; bone marrow transfer experiments show both hematopoietic and non-hematopoietic components are involved in Fn14-mediated colonic protection.","method":"Fn14-KO mice (DSS colitis and AOM/DSS tumor model), bone marrow chimera experiments, endoscopic and histological scoring","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with chimera experiments defining cell compartment specificity, single lab","pmids":["27634763"],"is_preprint":false},{"year":2018,"finding":"Visual experience (sensory-driven activity) induces Fn14 expression in excitatory thalamocortical neurons of the dorsal lateral geniculate nucleus; Fn14 is dispensable for early spontaneous activity-dependent refinement but is essential for later experience-dependent retinogeniculate refinement, mediating both functional and anatomical rearrangements in response to sensory experience.","method":"Single-nucleus RNA sequencing, electrophysiology, structural (retinogeniculate input) analysis, Fn14-KO mice (visual deprivation/experience paradigms)","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — single-nucleus RNA-seq identification + genetic KO with electrophysiological and structural validation, multiple orthogonal methods","pmids":["30033152"],"is_preprint":false},{"year":2018,"finding":"TRAF3IP2 mediates TWEAK/Fn14-induced pro-fibrotic responses in cardiac fibroblasts; TWEAK upregulates TRAF3IP2 in a positive feedback loop; TRAF3IP2 mediates TWEAK-induced p38 MAPK, NF-κB, and AP-1 activation; silencing TRAF3IP2 blocks TWEAK-induced collagen expression, MMP activation, and fibroblast proliferation/migration; TRAF3IP2-KO mice are protected from TWEAK-induced cardiac fibrosis in vivo.","method":"TRAF3IP2 siRNA, TRAF3IP2-KO mice, TWEAK infusion model, p38/NF-κB/AP-1 activation assay, collagen assay, migration assay","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 — siRNA + genetic KO + in vivo pharmacological model with multiple mechanistic pathway readouts","pmids":["29981796"],"is_preprint":false},{"year":2018,"finding":"TWEAK/Fn14 activation mediates burn wound healing; Fn14-deficient mice show delayed burn wound healing with suppressed inflammatory responses, growth factor production, and ECM synthesis; TWEAK/Fn14 enhances migration and cytokine production of dermal endothelial cells and fibroblasts, and promotes α-SMA and palladin expression in fibroblasts.","method":"Fn14-KO BALB/c mice (burn wound model), TWEAK stimulation of HUVEC/fibroblasts, Fn14 siRNA, cytokine measurement, α-SMA immunostaining","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO in vivo + siRNA in vitro with multiple cellular readouts, single lab","pmids":["30081003"],"is_preprint":false},{"year":2018,"finding":"TWEAK/Fn14 mediates atrial myocyte hypertrophy through activation of the JAK2/STAT3 signaling pathway; JAK2 or STAT3 siRNA inhibition attenuates TWEAK-induced HL-1 atrial myocyte hypertrophy markers (ANP, Troponin T).","method":"HL-1 atrial myocyte culture, TWEAK stimulation, Fn14 siRNA, JAK2/STAT3 siRNA, hypertrophy marker expression","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA pathway dissection with multiple hypertrophy readouts, single lab","pmids":["29971943"],"is_preprint":false},{"year":2019,"finding":"TWEAK/Fn14 pathway promotes VSMC proliferation and migration by upregulating cyclins (cyclin D1), CDK4/6, and downregulating p15INK4B via ERK and Akt activation; Fn14 or TWEAK genetic depletion and anti-TWEAK antibody reduce neointimal formation after wire injury; pharmacological inhibition of TWEAK reduces cyclin D1/CDK4/6 and increases p15INK4B in vivo.","method":"RNA-seq in VSMCs, Tnfrsf12a-KO VSMCs, wire injury mouse model, Tnfrsf12a/Tnfsf12 global KO, anti-TWEAK antibody, ERK/Akt inhibition, cell proliferation/migration assays","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 — RNA-seq + genetic KO + pharmacological blockade in vivo/in vitro with defined cell cycle mechanism","pmids":["31395500"],"is_preprint":false},{"year":2019,"finding":"Fn14 participates in neuropathic pain through NF-κB pathway in primary sensory neurons; spinal nerve ligation increases Fn14 expression in DRG; Fn14 knockdown attenuates pain hypersensitivity; Fn14 overexpression produces pain hypersensitivity; mechanistically, Fn14 promotes p65 nuclear translocation in injured DRG neurons.","method":"Spinal nerve ligation model, Fn14 siRNA (intrathecal), Fn14 overexpression, p65 nuclear translocation assay, pain behavior assays","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockdown and overexpression with NF-κB mechanism and behavioral readout, single lab","pmids":["30976982"],"is_preprint":false},{"year":2020,"finding":"TWEAK/Fn14 promotes macrophage recruitment and polarization to proinflammatory CD206+ phenotype; Fn14 drives cancer-associated fibroblast proliferation and collagen deposition in cholangiocarcinoma; MCP-1 (CCL2) is a pharmacologically targetable downstream mediator; genetic Fn14 ablation reduces inflammatory, fibrogenic, and ductular responses during TAA-induced carcinogenesis.","method":"Flow cytometry, conditioned medium macrophage polarization assay, Fn14-KO mice (TAA CCA model), TWEAK overexpression, CCA xenograft + MCP-1 blockade, proteomics","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic and pharmacological approaches with mechanistic pathway identification, multiple orthogonal methods","pmids":["33221352"],"is_preprint":false},{"year":2021,"finding":"TWEAK/Fn14 signaling promotes hepatocyte pyroptosis in cholestasis via the NFκB/Caspase-1/GSDMD signaling pathway; bile acids induce TNFRSF12A expression by enhancing c-JUN binding to the TNFRSF12A promoter; macrophage-secreted TWEAK enhances TNFRSF12A-induced pyroptosis; Tnfrsf12a-KO mice show reduced hepatocyte pyroptosis, NLRP3, cleaved-Caspase-1, and cleaved-GSDMD in cholestatic injury models.","method":"Tnfrsf12a-KO mice (BDL and DDC models), c-JUN ChIP on TNFRSF12A promoter, pyroptosis markers (NLRP3/cleaved-Caspase-1/GSDMD), CRISPR, luciferase reporter, macrophage conditioned medium experiments","journal":"Cell death discovery","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO + c-JUN ChIP demonstrating transcriptional regulation + mechanistic pyroptosis pathway with multiple orthogonal methods","pmids":["36690641"],"is_preprint":false},{"year":2023,"finding":"TWEAK/FN14 signaling in Prominin-1-expressing hepatic progenitor cells promotes their proliferation and profibrogenic ductular reactions via non-canonical NF-κB signaling; FN14 antagonism reduces ductular reactions, biliary fibrosis, and periportal fibroblast activation; recombinant TWEAK accelerates organoid growth, an effect abolished by FN14 antagonist L524-0366.","method":"RRV mouse model of biliary atresia, FN14 antagonist (L524-0366), murine HPC organoid culture, non-canonical NF-κB signaling assay, RNA-seq analysis","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological blockade in vivo + organoid gain/loss-of-function + pathway analysis, single lab","pmids":["36626628"],"is_preprint":false}],"current_model":"TNFRSF12A (Fn14) is a highly inducible, small type I transmembrane TNF receptor superfamily member that binds TWEAK (TNFSF12) as its primary ligand, triggering recruitment of TNFR-associated factors and activation of both canonical and non-canonical NF-κB pathways, as well as MAPK (ERK, p38, JNK), PI3K/Akt, JAK2/STAT3, and RhoA/MRTF-A signaling cascades, resulting in context-dependent cellular responses including proliferation, migration, differentiation inhibition, apoptosis/pyroptosis, inflammation, angiogenesis, and fibrosis; Fn14 can also self-associate via its cytoplasmic domain (cysteine 122 disulfide) to signal in a TWEAK-independent manner when highly expressed, physically interacts with FGFR-1 to co-regulate cardiomyocyte cell cycle re-entry, and its transcription is regulated by c-JUN (bile acids), SMAD4 (TGF-β), AR (androgen receptor), JNK (mechanical stress), and HIF-1α (hypoxia)."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing Fn14 as the sole physiological receptor for TWEAK resolved the identity of the cognate receptor-ligand pair and enabled all subsequent pathway studies.","evidence":"Receptor-ligand binding assays with recombinant proteins and cDNA transfection across multiple labs","pmids":["12787562","12821115"],"confidence":"High","gaps":["Crystal structure of the TWEAK–Fn14 complex not determined","Whether additional co-receptors exist remained open"]},{"year":2006,"claim":"Demonstration that TWEAK/Fn14 activates NF-κB to drive proinflammatory chemokine production, and separately promotes proliferation while inhibiting differentiation in myoblasts, established Fn14 as a bifunctional mediator of inflammation and tissue remodeling.","evidence":"Fn14-KO mice plus pharmacological NF-κB inhibition in mesangial cells, bronchial epithelial cells, and myoblasts; in vivo muscle regeneration and colitis models","pmids":["16424220","15120617","17124496"],"confidence":"High","gaps":["Whether canonical or non-canonical NF-κB mediates each cellular response was not yet resolved","Signaling intermediates between Fn14 and IκB phosphorylation were uncharacterized"]},{"year":2006,"claim":"Discovery that Fn14 also engages PI3K/Akt and MAPK/ERK pathways in osteoblasts revealed that Fn14 signaling is not limited to NF-κB.","evidence":"Pharmacological pathway inhibitors and Fn14-Fc neutralization in MC3T3-E1 osteoblastic cells","pmids":["16945157"],"confidence":"Medium","gaps":["Whether PI3K/Akt and ERK act in parallel or sequentially downstream of Fn14 was not resolved","Pathway engagement in primary osteoblasts not confirmed"]},{"year":2006,"claim":"Pharmacological (Fn14-Fc) and genetic (Fn14-KO) blockade in cerebral ischemia showed Fn14 controls blood-brain barrier integrity through NF-κB and MMP-9, establishing a pathogenic role in neuroinflammation.","evidence":"MCAO model with Fn14-Fc decoy and Fn14-KO mice; Evans blue extravasation, NF-κB/MMP-9 assays","pmids":["16835630","15681834"],"confidence":"High","gaps":["Direct Fn14 expression on BBB endothelial cells versus perivascular cells was not definitively shown in vivo"]},{"year":2008,"claim":"Genetic and antibody-based TWEAK/Fn14 blockade in colitis models defined an epithelial TWEAK–Fn14 axis driving intestinal inflammation and injury.","evidence":"TWEAK-KO and Fn14-KO mice in TNBS colitis and irradiation models; anti-TWEAK mAb","pmids":["19109961"],"confidence":"High","gaps":["Relative contribution of epithelial vs. immune cell Fn14 was not dissected with conditional KO"]},{"year":2013,"claim":"Discovery that Fn14 self-associates via a Cys-122 disulfide in its cytoplasmic domain and can activate NF-κB without TWEAK binding revealed a ligand-independent signaling mode that explains overexpression-driven effects in tumors and injured tissue.","evidence":"Deletion mutagenesis, co-immunoprecipitation under non-reducing conditions, NF-κB reporter assay","pmids":["23750247"],"confidence":"High","gaps":["Physiological contexts where TWEAK-independent signaling dominates remain uncharacterized","Stoichiometry of self-associated Fn14 complexes not determined"]},{"year":2013,"claim":"Demonstration that soluble TWEAK (trimeric) preferentially activates non-canonical NF-κB while membrane-bound TWEAK (higher-order) activates all pathways resolved how ligand valency differentially engages Fn14 signaling outputs.","evidence":"Comparison of soluble vs. membrane TWEAK and antibody oligomerization states with canonical/non-canonical NF-κB, IL-8, and cell death readouts","pmids":["23532848"],"confidence":"High","gaps":["Structural basis for valency-dependent signaling not established","Whether endogenous TWEAK processing rate controls pathway balance in vivo is unknown"]},{"year":2013,"claim":"Identification of RhoA/MRTF-A as a profibrotic Fn14 effector pathway in cardiac fibroblasts, complementing the established NF-κB axis, broadened the repertoire of Fn14 downstream signaling.","evidence":"Fn14-KO mice in pulmonary artery banding model; RhoA/MRTF-A pathway analysis in vitro","pmids":["23325387"],"confidence":"High","gaps":["How Fn14 activates RhoA (direct or indirect) is unknown","Whether RhoA/MRTF-A contributes to fibrosis in non-cardiac tissues is untested"]},{"year":2014,"claim":"Demonstration of physical FGFR-1–Fn14 interaction and synergistic PI3K/Akt signaling in cardiomyocyte cell cycle reentry established Fn14 as a co-receptor capable of heterotypic receptor crosstalk beyond conventional TNF receptor signaling.","evidence":"Co-immunoprecipitation, proximity ligation assay, kinase inhibitors, cell cycle assays in neonatal and adult cardiomyocytes","pmids":["24571920"],"confidence":"High","gaps":["Structural determinant of FGFR-1/Fn14 interaction not mapped","In vivo relevance for cardiac regeneration not shown"]},{"year":2014,"claim":"Mechanistic dissection of Fn14 in muscle atrophy revealed activation of NF-κB, ubiquitin-proteasome, autophagy, caspase proteolysis, and PGC-1α suppression as a coordinated proteolytic and metabolic program, linking Fn14 to sarcopenia and muscle wasting.","evidence":"TWEAK-Tg, Fn14-KO, PGC-1α-Tg mice; denervation model; proteasome, autophagy, and fiber-type assays","pmids":["24478779","24327607","24680686"],"confidence":"High","gaps":["Whether Fn14 acts cell-autonomously in myofibers was not resolved with conditional KO","Therapeutic window for Fn14 inhibition in atrophy not defined"]},{"year":2015,"claim":"Identification of SMAD4 binding to the Fn14 promoter positioned Fn14 as a TGF-β transcriptional target driving fibroblast activation, while AR binding to the Fn14 enhancer suppresses expression, defining opposing transcriptional regulatory inputs.","evidence":"SMAD4 ChIP on Fn14 promoter; AR ChIP on Fn14 enhancer; siRNA and overexpression in fibroblasts and prostate cancer cells","pmids":["26625141","24970477"],"confidence":"Medium","gaps":["Integration of SMAD4 and AR regulation on the same promoter not tested","Other transcription factors at the Fn14 locus remain poorly characterized"]},{"year":2018,"claim":"Discovery that visual experience induces Fn14 in thalamocortical neurons and that Fn14 is required for experience-dependent retinogeniculate refinement established a neuronal function for Fn14 beyond inflammation and tissue remodeling.","evidence":"Single-nucleus RNA-seq, Fn14-KO mice with visual deprivation paradigms, electrophysiology, anatomical tracing","pmids":["30033152"],"confidence":"High","gaps":["Downstream signaling pathway in neurons (NF-κB or other) is not defined","Whether TWEAK is the relevant ligand in this synaptic context is unknown"]},{"year":2018,"claim":"Identification of TRAF3IP2 as a mediator linking Fn14 to p38 MAPK, NF-κB, and AP-1 in cardiac fibroblasts, with TRAF3IP2-KO mice protected from TWEAK-induced cardiac fibrosis, placed TRAF3IP2 as a proximal signaling adaptor.","evidence":"TRAF3IP2 siRNA and TRAF3IP2-KO mice; TWEAK infusion model; p38/NF-κB/AP-1 activation assays","pmids":["29981796"],"confidence":"High","gaps":["Whether TRAF3IP2 binds Fn14 directly or through an intermediary TRAF is not shown","Generalizability of TRAF3IP2 dependence to non-cardiac Fn14 signaling is untested"]},{"year":2021,"claim":"Demonstration that bile acids induce Fn14 via c-JUN and that TWEAK/Fn14 drives hepatocyte pyroptosis through NF-κB/Caspase-1/GSDMD added pyroptosis to the Fn14 cell death repertoire and identified a cholestasis-specific transcriptional input.","evidence":"Tnfrsf12a-KO mice in BDL and DDC models; c-JUN ChIP; pyroptosis markers (NLRP3, cleaved Caspase-1, GSDMD); CRISPR","pmids":["36690641"],"confidence":"High","gaps":["Whether Fn14 activates NLRP3 directly or through NF-κB-dependent transcriptional priming is not fully resolved","Relevance beyond murine cholestasis models not tested"]},{"year":2023,"claim":"Pharmacological FN14 antagonism reduced ductular reactions and biliary fibrosis driven by hepatic progenitor cells via non-canonical NF-κB, demonstrating Fn14 as a druggable target in biliary disease and linking it to progenitor cell biology.","evidence":"FN14 antagonist L524-0366 in RRV biliary atresia model; HPC organoid culture; non-canonical NF-κB and RNA-seq","pmids":["36626628"],"confidence":"Medium","gaps":["Selectivity and pharmacokinetics of L524-0366 not fully characterized","Whether progenitor cell Fn14 function extends to other liver injury contexts is unknown"]},{"year":null,"claim":"The structural basis of TWEAK–Fn14 interaction and how receptor clustering geometry dictates canonical vs. non-canonical NF-κB selectivity remain unresolved; conditional knockout studies have not dissected cell-type-autonomous Fn14 functions in most tissues; the mechanism by which Fn14 activates RhoA, the identity of neuronal Fn14 signaling partners, and the full spectrum of Fn14 adaptors beyond TRAF and TRAF3IP2 are open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of TWEAK–Fn14 complex","Conditional knockout studies lacking for most tissues","Neuronal Fn14 signaling mechanism undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2,5,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[25,34]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,13,15]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,7,16,25,34,36,37,40]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,8,19,20,39]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,11,12,40]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[10,37]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[14,17,31,34,35]}],"complexes":[],"partners":["TNFSF12","FGFR1","TRAF3IP2","NFKB1","RELA"],"other_free_text":[]},"mechanistic_narrative":"TNFRSF12A (Fn14) is an inducible type I transmembrane receptor of the TNF receptor superfamily that serves as the sole receptor for TWEAK (TNFSF12) and functions as a central mediator of inflammation, tissue remodeling, cell proliferation, and cell death across diverse tissues. TWEAK binding activates canonical and non-canonical NF-κB pathways—with ligand valency determining pathway selectivity—as well as MAPK (ERK, p38, JNK), PI3K/Akt, JAK2/STAT3, and RhoA/MRTF-A cascades, driving context-dependent outcomes including chemokine/cytokine production, fibroblast collagen synthesis, myoblast proliferation with differentiation inhibition, skeletal muscle atrophy via the ubiquitin-proteasome and autophagy systems, hepatocyte pyroptosis through NF-κB/Caspase-1/GSDMD, and vascular smooth muscle cell proliferation [PMID:12787562, PMID:16424220, PMID:23532848, PMID:17124496, PMID:24478779, PMID:36690641, PMID:31395500]. Fn14 can also signal independently of TWEAK through cytoplasmic domain–mediated self-association via a Cys-122 disulfide bond, physically interacts with FGFR-1 to co-activate PI3K/Akt-dependent cardiomyocyte cell cycle reentry, and its transcription is regulated by c-JUN, SMAD4, androgen receptor, and JNK-dependent pathways [PMID:23750247, PMID:24571920, PMID:36690641, PMID:26625141, PMID:24970477, PMID:24446436]. In the nervous system, Fn14 is required for experience-dependent retinogeniculate circuit refinement and participates in neuropathic pain through NF-κB-dependent signaling in sensory neurons [PMID:30033152, PMID:30976982]."},"prefetch_data":{"uniprot":{"accession":"Q9NP84","full_name":"Tumor necrosis factor receptor superfamily member 12A","aliases":["Fibroblast growth factor-inducible immediate-early response protein 14","FGF-inducible 14","Tweak-receptor","TweakR"],"length_aa":129,"mass_kda":13.9,"function":"Receptor for TNFSF12/TWEAK. Weak inducer of apoptosis in some cell types. Promotes angiogenesis and the proliferation of endothelial cells. May modulate cellular adhesion to matrix proteins","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9NP84/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TNFRSF12A","classification":"Not Classified","n_dependent_lines":34,"n_total_lines":1208,"dependency_fraction":0.028145695364238412},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TNFRSF12A","total_profiled":1310},"omim":[{"mim_id":"605914","title":"TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY, MEMBER 12A; TNFRSF12A","url":"https://www.omim.org/entry/605914"},{"mim_id":"602695","title":"TUMOR NECROSIS FACTOR LIGAND SUPERFAMILY, MEMBER 12; TNFSF12","url":"https://www.omim.org/entry/602695"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TNFRSF12A"},"hgnc":{"alias_symbol":["FN14","TweakR","CD266"],"prev_symbol":[]},"alphafold":{"accession":"Q9NP84","domains":[{"cath_id":"4.10.400.20","chopping":"36-70","consensus_level":"medium","plddt":83.6606,"start":36,"end":70},{"cath_id":"1.20.5","chopping":"71-107","consensus_level":"medium","plddt":78.98,"start":71,"end":107}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NP84","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NP84-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NP84-F1-predicted_aligned_error_v6.png","plddt_mean":73.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TNFRSF12A","jax_strain_url":"https://www.jax.org/strain/search?query=TNFRSF12A"},"sequence":{"accession":"Q9NP84","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NP84.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NP84/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NP84"}},"corpus_meta":[{"pmid":"18404150","id":"PMC_18404150","title":"The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting.","date":"2008","source":"Nature reviews. 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    \"journal\": \"Cytokine & growth factor reviews\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — foundational receptor identification, replicated across multiple labs and cited >250 times\",\n      \"pmids\": [\"12787562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Murine TWEAK binds to murine Fn14 transfectants and induces cell death; macrophages secrete functional soluble TWEAK; Fn14 overexpression confers sensitivity to TWEAK-induced cytotoxicity.\",\n      \"method\": \"cDNA transfection, monoclonal antibody generation, cell death assay, functional neutralization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding and functional assay in transfected cells, single study\",\n      \"pmids\": [\"12821115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TWEAK binding to Fn14 on human bronchial epithelial cells induces IL-8 and GM-CSF production through IκBα phosphorylation and NF-κB activation; anti-Fn14 blocking antibody abrogates this effect.\",\n      \"method\": \"Cell stimulation assay, blocking antibody, IκBα phosphorylation assay, NF-κB inhibitor (BAY11-7082)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition and blocking antibody confirm Fn14-dependent NF-κB pathway, single lab\",\n      \"pmids\": [\"15120617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Intracerebroventricular injection of soluble Fn14-Fc decoy receptor after middle cerebral artery occlusion significantly reduces infarct volume, microglial activation, and apoptotic cell death in the ischemic penumbra, demonstrating TWEAK plays a pathogenic role in ischemia-induced brain injury.\",\n      \"method\": \"Murine MCAO model, intracerebroventricular injection of Fn14-Fc decoy receptor, histopathology, ELISA\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with decoy receptor and defined phenotypic readout, single study\",\n      \"pmids\": [\"15681834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TWEAK/Fn14 pathway inhibition (via soluble Fn14-Fc decoy receptor or genetic Fn14 deficiency) reduces blood-brain barrier permeability, NF-κB activation, MMP-9 activation, and basement membrane laminin degradation after cerebral ischemia, identifying Fn14 as a regulator of neurovascular unit integrity.\",\n      \"method\": \"Murine MCAO model, Fn14-Fc decoy receptor, Fn14 knockout mice, Evans blue dye extravasation, NF-κB/MMP-9 assays\",\n      \"journal\": \"Journal of cerebral blood flow and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic loss-of-function, multiple orthogonal readouts, replicated findings\",\n      \"pmids\": [\"16835630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TWEAK stimulation of mesangial cells expressing Fn14 induces NF-κB pathway activation (phosphorylated IκB) and dose-dependent chemokine secretion (CCL2, CCL5, CXCL10, CXCL1); Fn14-deficient mesangial cells and Fn14-knockout mice confirm Fn14 dependence of these proinflammatory effects.\",\n      \"method\": \"Cell stimulation, IκB phosphorylation assay, NF-κB inhibitor, Fn14-KO cells and mice, ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition + genetic KO confirmation + in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"16424220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TWEAK, via Fn14, promotes proliferation and inhibits terminal differentiation of mesenchymal stem cells and primary mouse muscle myoblasts through NF-κB activation; Fn14-deficient myoblasts show reduced proliferative capacity and altered myotube formation; Fn14-KO mice display delayed skeletal muscle regeneration after cardiotoxin injury.\",\n      \"method\": \"In vitro myoblast culture, Fn14-KO mouse generation, NF-κB activation assay, cardiotoxin-injection regeneration model, histology\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple in vitro and in vivo phenotypes, >190 citations\",\n      \"pmids\": [\"17124496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TWEAK/Fn14 interaction in osteoblastic MC3T3-E1 cells induces RANTES production via PI3K-Akt (not NF-κB), inhibits BMP-2-induced osteoblast differentiation via MAPK/Erk, and upregulates RANKL expression via MAPK/Erk; all effects abolished by Fn14-Fc chimera.\",\n      \"method\": \"Cell stimulation, pathway inhibitors, osteoblast differentiation markers, Fn14-Fc chimera neutralization\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling pathways defined with pharmacological inhibitors and receptor-Fc neutralization, single lab\",\n      \"pmids\": [\"16945157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TWEAK/Fn14 pathway deficiency (TWEAK-KO or Fn14-KO mice) or anti-TWEAK antibody reduces colitis severity, neutrophil/macrophage infiltration, chemokine/cytokine/MMP expression, and intestinal epithelial cell death after gamma-irradiation; Fn14 is expressed on colon epithelial cells and TWEAK induces epithelial production of inflammatory mediators, defining a TWEAK-intestinal epithelial cell axis.\",\n      \"method\": \"TNBS colitis model, TWEAK-KO and Fn14-KO mice, anti-TWEAK mAb, gene expression profiling, gamma-irradiation injury model\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic KO models, pharmacological blockade, and mechanistic in vitro studies, >60 citations\",\n      \"pmids\": [\"19109961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Fn14-Fc fusion protein (TWEAK inhibitor) treatment in ApoE-/- mice reduces atherosclerotic plaque features; TWEAK/Fn14 signaling mediates lipid uptake in macrophages in vitro, implicating Fn14 in macrophage foam cell biology.\",\n      \"method\": \"ApoE-/- mouse model, Fn14-Fc treatment, plaque morphometry, in vitro macrophage lipid uptake assay\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo pharmacological blockade + in vitro mechanistic assay, single study\",\n      \"pmids\": [\"19762780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Soluble TWEAK induces inflammatory cytokine secretion, MMP-9 production/activation, and expression of cell adhesion molecules in human cerebral microvascular endothelial cells (BBB model), and increases HCMEC monolayer permeability, demonstrating Fn14-mediated disruption of blood-brain barrier integrity.\",\n      \"method\": \"In vitro BBB model (HCMEC cultures), TWEAK stimulation, cytokine ELISA, MMP assay, permeability assay\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — in vitro BBB model with multiple functional readouts, single lab\",\n      \"pmids\": [\"23320797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-13-induced intestinal epithelial cell apoptosis (caspase-3 activation) requires TWEAK, Fn14, and ADAM17-mediated endogenous TNF-α secretion; similarly, TNF-α-induced caspase activation requires IL-13, TWEAK, and Fn14, revealing a cooperative IL-13–TWEAK/Fn14–TNF-α axis in mucosal damage.\",\n      \"method\": \"Intestinal explant cultures from TWEAK-KO mice, caspase-3 activation assay, ADAM17 inhibition, gene expression profiling\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO, pharmacological inhibition, and multiple orthogonal mechanistic readouts in single study\",\n      \"pmids\": [\"21893119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Anti-Fn14 agonistic antibody (BIIB036) activates Fn14 signaling, promotes tumor cell apoptosis, and inhibits tumor growth in vivo; increasing antibody valency enhances anti-tumor effect, suggesting higher-order Fn14 receptor cross-linking is required for full agonism; full Fc effector function is required for maximal in vivo activity.\",\n      \"method\": \"Fn14 signaling assay, in vitro apoptosis assay, multiple xenograft models, valency manipulation, Fc variant comparison\",\n      \"journal\": \"mAbs\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic antibody characterization with multiple in vitro and in vivo models, single lab\",\n      \"pmids\": [\"21697654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Anti-Fn14 antibody (ITEM-4) conjugated to recombinant gelonin (ITEM4-rGel) specifically internalizes into Fn14-positive tumor cells within 2 hours, demonstrating that Fn14 undergoes receptor-mediated internalization; the immunoconjugate kills Fn14-expressing cells via apoptosis with HMGB1 release.\",\n      \"method\": \"Confocal microscopy internalization assay, cytotoxicity assay, apoptosis detection, xenograft tumor model\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct internalization imaging with functional cytotoxicity readout, single lab\",\n      \"pmids\": [\"21586630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TWEAK/Fn14 axis promotes cardiac fibroblast proliferation and collagen synthesis via NF-κB pathway activation and subsequent MMP-9 upregulation; siRNA silencing of Fn14 inhibits TWEAK-induced NF-κB activation, proliferation, and collagen synthesis.\",\n      \"method\": \"Neonatal rat cardiac fibroblast culture, siRNA knockdown of Fn14, NF-κB activation assay, MMP-9 measurement, collagen synthesis assay\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown with multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"22555979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fn14 undergoes TWEAK-independent self-association into dimers mediated by an 18-amino acid region within its cytoplasmic domain; an intermolecular disulfide bond at cysteine residue 122 mediates Fn14 dimerization; a TWEAK-binding-deficient Fn14 deletion mutant can still activate the NF-κB pathway in transfected cells, demonstrating TWEAK-independent Fn14 signaling.\",\n      \"method\": \"Deletion mutagenesis, co-immunoprecipitation, SDS-PAGE under non-reducing conditions, NF-κB reporter assay, transfection\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with biochemical reconstitution of dimerization and functional NF-κB assay in single study\",\n      \"pmids\": [\"23750247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Anti-Fn14 antibodies (PDL192 and P4A8) selectively activate the alternative (non-canonical) NF-κB pathway but not classical NF-κB, IL-8 production, or cell death; oligomerization or FcγR-binding converts these antibodies into full Fn14 agonists mimicking membrane TWEAK; soluble TWEAK predominantly triggers alternative NF-κB and enhances TNF-induced cell death, while membrane TWEAK activates all Fn14-associated pathways, demonstrating valency-dependent differential Fn14 signaling.\",\n      \"method\": \"NFκB pathway analysis (p100 processing, classical NF-κB), IL-8 ELISA, cell death assay, protein G oligomerization, FcγR-binding, soluble vs. membrane TWEAK comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal signaling readouts comparing different ligand forms and antibody valencies, mechanistically rigorous\",\n      \"pmids\": [\"23532848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fn14 activation in cardiac fibroblasts induces collagen expression via RhoA-dependent nuclear translocation of myocardin-related transcription factor-A (MRTF-A)/MAL; Fn14-deficient mice show substantially reduced RV fibrosis and dysfunction after pulmonary artery banding; Fn14 expression in cardiac fibroblasts is regulated by endothelin-1.\",\n      \"method\": \"Fn14-KO mice (PAB model), cell culture RhoA/MRTF-A pathway analysis, fibroblast proliferation/differentiation assay, endothelin-1 treatment\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in vivo + mechanistic pathway identification in vitro, multiple orthogonal methods\",\n      \"pmids\": [\"23325387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TWEAK reduces PGC-1α levels and mitochondrial content (~50%) in skeletal muscle; PGC-1α overexpression inhibits TWEAK-induced NF-κB activation (~50%) and dramatically reduces atrogene (MAFbx/MuRF1) expression (~90%); PGC-1α overexpression also prevents inducible Fn14 expression in denervated muscle, demonstrating a regulatory circuit between TWEAK-Fn14 signaling and PGC-1α in muscle atrophy.\",\n      \"method\": \"TWEAK-Tg mice, Fn14-KO mice, TWEAK-KO mice, PGC-1α transgenic mice, denervation model, NF-κB activity assay, gene expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic mouse models with mechanistic NF-κB and atrogene pathway readouts, multiple orthogonal approaches\",\n      \"pmids\": [\"24327607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TWEAK/Fn14 pathway activation in chronic colitis promotes Th2-type immunity and fibrosis through upregulation of TSLP in colon epithelial cells; IL-13 potentiates TWEAK-induced TSLP production; TWEAK and IL-13 synergistically promote fibroblast proliferation; Fn14-KO mice show reduced inflammation, fibrosis, and TSLP in chronic colitis model.\",\n      \"method\": \"Fn14-KO mice (chronic colitis model), TSLP receptor-KO mice, colon explant TSLP assay, fibroblast proliferation assay\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic KO models + mechanistic in vitro assays defining IL-13–TWEAK–TSLP axis\",\n      \"pmids\": [\"23462911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fn14 is expressed in podocytes and is upregulated by inflammatory cytokines; TWEAK activates NF-κB in cultured podocytes and increases MCP-1 production via NFκB (blocked by parthenolide); Fn14-KO mice with protein overload proteinuria show reduced glomerular macrophage infiltration and MCP-1 levels.\",\n      \"method\": \"Podocyte cell culture, NFκB inhibitor, Fn14-KO mice (protein overload proteinuria model), adenovirus-mediated TWEAK overexpression in mice, macrophage infiltration assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition + in vivo genetic and viral gain/loss-of-function approaches\",\n      \"pmids\": [\"23999007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TWEAK/Fn14 signaling activates canonical NF-κB pathway to promote myoblast proliferation and inhibit myogenesis, while also activating non-canonical NF-κB to promote myoblast fusion; both pathways are regulated by cIAP1, which is an essential downstream signaling component of Fn14.\",\n      \"method\": \"NF-κB pathway analysis (canonical vs. non-canonical), cIAP1 characterization, myoblast proliferation/differentiation/fusion assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway dissection with canonical vs. non-canonical NF-κB readouts, review with synthesis of multiple mechanistic studies\",\n      \"pmids\": [\"24550918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FN14 promotes prostate cancer bone metastasis through IKKβ-dependent NF-κB signaling; FN14 expression is inversely correlated with androgen receptor (AR) signaling output; AR binding to the FN14 enhancer decreases FN14 expression, defining an upstream regulatory mechanism.\",\n      \"method\": \"In vivo bone metastasis model with FN14 depletion, FN14 reconstitution with IKKβ, AR ChIP (AR binding to FN14 enhancer), NF-κB signaling assay, clinical sample correlation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo functional reconstitution and ChIP demonstrating AR regulation of Fn14, single lab\",\n      \"pmids\": [\"24970477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Large-magnitude (12%) cyclic mechanical stretch activates Ca2+ influx → ROS generation → ASK1-JNK pathway → transient Fn14 upregulation in MC3T3-E1 osteoblasts; cells with elevated Fn14 then acquire sensitivity to TWEAK-induced apoptosis; small-magnitude stretch (1%) activates ERK promoting osteogenic gene expression without Fn14 upregulation.\",\n      \"method\": \"Cyclic stretch assay, ROS measurement, kinase pathway inhibitors, JNK/p38/ERK activation assays, Fn14 expression measurement, apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway dissection with pharmacological inhibitors and functional outcome, single lab\",\n      \"pmids\": [\"24446436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TWEAK/Fn14 axis mediates skeletal muscle atrophy by activating NF-κB signaling and upregulating ubiquitin-proteasome system, autophagy, and caspase-mediated proteolysis; TWEAK also causes slow-to-fast fiber type transition and represses mitochondrial content and oxidative phosphorylation capacity.\",\n      \"method\": \"In vitro myotube atrophy assay, NF-κB activation, proteasome assay, autophagy markers, fiber-type analysis, mitochondrial content measurement; TWEAK-Tg and Fn14-KO mouse models\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo genetic models with diverse mechanistic readouts, extensively replicated\",\n      \"pmids\": [\"24478779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FGFR-1 and Fn14 physically interact (co-immunoprecipitation and proximity ligation assay) in cardiomyocytes; FGF1-induced cardiomyocyte cell cycle reentry is blocked by Fn14 inhibition, and TWEAK-induced cell cycle activation is blocked by FGFR-1 inhibition; FGF1 and TWEAK act synergistically via PI3K/Akt signaling to induce cell cycle reentry; the FGFR-1/Fn14 interaction is enhanced in the presence of both ligands.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, kinase inhibitors, Fn14 overexpression, cell cycle reentry assay in neonatal and adult cardiomyocytes, PI3K/Akt inhibition\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct protein-protein interaction by two independent methods + functional mutagenesis/inhibition + mechanistic PI3K/Akt pathway\",\n      \"pmids\": [\"24571920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TWEAK/Fn14 signaling promotes NSCLC cell survival via NF-κB-dependent upregulation of Mcl-1; TWEAK-induced chemo- and radioresistance is Mcl-1-dependent; Mcl-1 inhibition (EU-5148) or siRNA depletion sensitizes TWEAK-treated NSCLC cells to cisplatin or radiation; Bcl-2/Bcl-xL inhibition had minimal effect.\",\n      \"method\": \"TWEAK stimulation, NF-κB activation assay, Mcl-1 siRNA, pharmacological Mcl-1 inhibitor (EU-5148), cisplatin/radiation survival assay\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA and pharmacological inhibition with multiple functional readouts, single lab\",\n      \"pmids\": [\"24469836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Fn14 genetic deletion reduces muscle pathology and improves function in a mouse model of RNA toxicity (DM1); anti-TWEAK antibody treatment similarly improves muscle histopathology and function; Fn14 induction in DM1 is associated with downstream NF-κB pathway activation.\",\n      \"method\": \"Fn14-KO mice in RNA toxicity model, anti-TWEAK antibody treatment, NF-κB signaling assay, muscle histopathology, functional outcome measures\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and pharmacological blockade with mechanistic NF-κB pathway assay, single study\",\n      \"pmids\": [\"25504044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Fn14 levels are increased in aged (18-month) mouse skeletal muscle; Fn14-KO blunts age-associated fiber atrophy and reduces NF-κB activity, ubiquitinated protein levels, autophagy-related Atg12 expression, inflammatory gene expression, and interstitial fibrosis in aged muscle.\",\n      \"method\": \"Fn14-KO mice (aging model), NF-κB DNA-binding assay, ubiquitin/autophagy markers, fiber morphometry, histology\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple molecular and histological readouts, single study\",\n      \"pmids\": [\"24680686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TWEAK/Fn14 pathway is activated after resistance exercise in human skeletal muscle; Fn14 gene and protein expression peaks at 8–12 h post-resistance exercise; downstream markers indicate signaling through the alternative (non-canonical) NF-κB pathway; running exercise induces Fn14 to a much lesser extent, indicating exercise mode dependency.\",\n      \"method\": \"Human skeletal muscle biopsies, gene and protein expression time course, alternative NF-κB pathway markers\",\n      \"journal\": \"Journal of applied physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human in vivo temporal expression with pathway markers, single study\",\n      \"pmids\": [\"25539934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Fn14 expressed in tumors (not host) causes cancer-induced cachexia; tumors in Fn14- and TWEAK-deficient hosts develop comparable cachexia to wild-type, while anti-Fn14 antibodies prevent tumor-induced inflammation, fat and muscle mass loss, and dramatically extend lifespan.\",\n      \"method\": \"Fn14-KO and TWEAK-KO host mice, anti-Fn14 antibodies, tumor implantation models, body composition analysis, survival studies\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological dissection of tumor vs. host Fn14, multiple orthogonal approaches, high-impact journal\",\n      \"pmids\": [\"26359988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TGF-β signaling increases Fn14 expression through SMAD4 binding to the Fn14 promoter; Fn14 siRNA blocks extracellular matrix gene expression and fibroblast activation even in the presence of TGF-β1; Fn14 overexpression increases ECM gene expression, positioning Fn14 as a TGF-β/SMAD4 transcriptional target that drives fibroblast activation.\",\n      \"method\": \"SMAD4 ChIP on Fn14 promoter, Fn14 siRNA, Fn14 overexpression, ECM/collagen gene expression assay in dermal fibroblasts\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP demonstrating SMAD4 binding to Fn14 promoter, combined with functional siRNA and overexpression studies\",\n      \"pmids\": [\"26625141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fn14 plays a protective role during acute intestinal inflammation; Fn14-/- mice have enhanced susceptibility to DSS colitis and develop colonic tumors; bone marrow transfer experiments show both hematopoietic and non-hematopoietic components are involved in Fn14-mediated colonic protection.\",\n      \"method\": \"Fn14-KO mice (DSS colitis and AOM/DSS tumor model), bone marrow chimera experiments, endoscopic and histological scoring\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with chimera experiments defining cell compartment specificity, single lab\",\n      \"pmids\": [\"27634763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Visual experience (sensory-driven activity) induces Fn14 expression in excitatory thalamocortical neurons of the dorsal lateral geniculate nucleus; Fn14 is dispensable for early spontaneous activity-dependent refinement but is essential for later experience-dependent retinogeniculate refinement, mediating both functional and anatomical rearrangements in response to sensory experience.\",\n      \"method\": \"Single-nucleus RNA sequencing, electrophysiology, structural (retinogeniculate input) analysis, Fn14-KO mice (visual deprivation/experience paradigms)\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — single-nucleus RNA-seq identification + genetic KO with electrophysiological and structural validation, multiple orthogonal methods\",\n      \"pmids\": [\"30033152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRAF3IP2 mediates TWEAK/Fn14-induced pro-fibrotic responses in cardiac fibroblasts; TWEAK upregulates TRAF3IP2 in a positive feedback loop; TRAF3IP2 mediates TWEAK-induced p38 MAPK, NF-κB, and AP-1 activation; silencing TRAF3IP2 blocks TWEAK-induced collagen expression, MMP activation, and fibroblast proliferation/migration; TRAF3IP2-KO mice are protected from TWEAK-induced cardiac fibrosis in vivo.\",\n      \"method\": \"TRAF3IP2 siRNA, TRAF3IP2-KO mice, TWEAK infusion model, p38/NF-κB/AP-1 activation assay, collagen assay, migration assay\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA + genetic KO + in vivo pharmacological model with multiple mechanistic pathway readouts\",\n      \"pmids\": [\"29981796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TWEAK/Fn14 activation mediates burn wound healing; Fn14-deficient mice show delayed burn wound healing with suppressed inflammatory responses, growth factor production, and ECM synthesis; TWEAK/Fn14 enhances migration and cytokine production of dermal endothelial cells and fibroblasts, and promotes α-SMA and palladin expression in fibroblasts.\",\n      \"method\": \"Fn14-KO BALB/c mice (burn wound model), TWEAK stimulation of HUVEC/fibroblasts, Fn14 siRNA, cytokine measurement, α-SMA immunostaining\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in vivo + siRNA in vitro with multiple cellular readouts, single lab\",\n      \"pmids\": [\"30081003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TWEAK/Fn14 mediates atrial myocyte hypertrophy through activation of the JAK2/STAT3 signaling pathway; JAK2 or STAT3 siRNA inhibition attenuates TWEAK-induced HL-1 atrial myocyte hypertrophy markers (ANP, Troponin T).\",\n      \"method\": \"HL-1 atrial myocyte culture, TWEAK stimulation, Fn14 siRNA, JAK2/STAT3 siRNA, hypertrophy marker expression\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA pathway dissection with multiple hypertrophy readouts, single lab\",\n      \"pmids\": [\"29971943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TWEAK/Fn14 pathway promotes VSMC proliferation and migration by upregulating cyclins (cyclin D1), CDK4/6, and downregulating p15INK4B via ERK and Akt activation; Fn14 or TWEAK genetic depletion and anti-TWEAK antibody reduce neointimal formation after wire injury; pharmacological inhibition of TWEAK reduces cyclin D1/CDK4/6 and increases p15INK4B in vivo.\",\n      \"method\": \"RNA-seq in VSMCs, Tnfrsf12a-KO VSMCs, wire injury mouse model, Tnfrsf12a/Tnfsf12 global KO, anti-TWEAK antibody, ERK/Akt inhibition, cell proliferation/migration assays\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNA-seq + genetic KO + pharmacological blockade in vivo/in vitro with defined cell cycle mechanism\",\n      \"pmids\": [\"31395500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fn14 participates in neuropathic pain through NF-κB pathway in primary sensory neurons; spinal nerve ligation increases Fn14 expression in DRG; Fn14 knockdown attenuates pain hypersensitivity; Fn14 overexpression produces pain hypersensitivity; mechanistically, Fn14 promotes p65 nuclear translocation in injured DRG neurons.\",\n      \"method\": \"Spinal nerve ligation model, Fn14 siRNA (intrathecal), Fn14 overexpression, p65 nuclear translocation assay, pain behavior assays\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdown and overexpression with NF-κB mechanism and behavioral readout, single lab\",\n      \"pmids\": [\"30976982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TWEAK/Fn14 promotes macrophage recruitment and polarization to proinflammatory CD206+ phenotype; Fn14 drives cancer-associated fibroblast proliferation and collagen deposition in cholangiocarcinoma; MCP-1 (CCL2) is a pharmacologically targetable downstream mediator; genetic Fn14 ablation reduces inflammatory, fibrogenic, and ductular responses during TAA-induced carcinogenesis.\",\n      \"method\": \"Flow cytometry, conditioned medium macrophage polarization assay, Fn14-KO mice (TAA CCA model), TWEAK overexpression, CCA xenograft + MCP-1 blockade, proteomics\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological approaches with mechanistic pathway identification, multiple orthogonal methods\",\n      \"pmids\": [\"33221352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TWEAK/Fn14 signaling promotes hepatocyte pyroptosis in cholestasis via the NFκB/Caspase-1/GSDMD signaling pathway; bile acids induce TNFRSF12A expression by enhancing c-JUN binding to the TNFRSF12A promoter; macrophage-secreted TWEAK enhances TNFRSF12A-induced pyroptosis; Tnfrsf12a-KO mice show reduced hepatocyte pyroptosis, NLRP3, cleaved-Caspase-1, and cleaved-GSDMD in cholestatic injury models.\",\n      \"method\": \"Tnfrsf12a-KO mice (BDL and DDC models), c-JUN ChIP on TNFRSF12A promoter, pyroptosis markers (NLRP3/cleaved-Caspase-1/GSDMD), CRISPR, luciferase reporter, macrophage conditioned medium experiments\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO + c-JUN ChIP demonstrating transcriptional regulation + mechanistic pyroptosis pathway with multiple orthogonal methods\",\n      \"pmids\": [\"36690641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TWEAK/FN14 signaling in Prominin-1-expressing hepatic progenitor cells promotes their proliferation and profibrogenic ductular reactions via non-canonical NF-κB signaling; FN14 antagonism reduces ductular reactions, biliary fibrosis, and periportal fibroblast activation; recombinant TWEAK accelerates organoid growth, an effect abolished by FN14 antagonist L524-0366.\",\n      \"method\": \"RRV mouse model of biliary atresia, FN14 antagonist (L524-0366), murine HPC organoid culture, non-canonical NF-κB signaling assay, RNA-seq analysis\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological blockade in vivo + organoid gain/loss-of-function + pathway analysis, single lab\",\n      \"pmids\": [\"36626628\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TNFRSF12A (Fn14) is a highly inducible, small type I transmembrane TNF receptor superfamily member that binds TWEAK (TNFSF12) as its primary ligand, triggering recruitment of TNFR-associated factors and activation of both canonical and non-canonical NF-κB pathways, as well as MAPK (ERK, p38, JNK), PI3K/Akt, JAK2/STAT3, and RhoA/MRTF-A signaling cascades, resulting in context-dependent cellular responses including proliferation, migration, differentiation inhibition, apoptosis/pyroptosis, inflammation, angiogenesis, and fibrosis; Fn14 can also self-associate via its cytoplasmic domain (cysteine 122 disulfide) to signal in a TWEAK-independent manner when highly expressed, physically interacts with FGFR-1 to co-regulate cardiomyocyte cell cycle re-entry, and its transcription is regulated by c-JUN (bile acids), SMAD4 (TGF-β), AR (androgen receptor), JNK (mechanical stress), and HIF-1α (hypoxia).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TNFRSF12A (Fn14) is an inducible type I transmembrane receptor of the TNF receptor superfamily that serves as the sole receptor for TWEAK (TNFSF12) and functions as a central mediator of inflammation, tissue remodeling, cell proliferation, and cell death across diverse tissues. TWEAK binding activates canonical and non-canonical NF-κB pathways—with ligand valency determining pathway selectivity—as well as MAPK (ERK, p38, JNK), PI3K/Akt, JAK2/STAT3, and RhoA/MRTF-A cascades, driving context-dependent outcomes including chemokine/cytokine production, fibroblast collagen synthesis, myoblast proliferation with differentiation inhibition, skeletal muscle atrophy via the ubiquitin-proteasome and autophagy systems, hepatocyte pyroptosis through NF-κB/Caspase-1/GSDMD, and vascular smooth muscle cell proliferation [PMID:12787562, PMID:16424220, PMID:23532848, PMID:17124496, PMID:24478779, PMID:36690641, PMID:31395500]. Fn14 can also signal independently of TWEAK through cytoplasmic domain–mediated self-association via a Cys-122 disulfide bond, physically interacts with FGFR-1 to co-activate PI3K/Akt-dependent cardiomyocyte cell cycle reentry, and its transcription is regulated by c-JUN, SMAD4, androgen receptor, and JNK-dependent pathways [PMID:23750247, PMID:24571920, PMID:36690641, PMID:26625141, PMID:24970477, PMID:24446436]. In the nervous system, Fn14 is required for experience-dependent retinogeniculate circuit refinement and participates in neuropathic pain through NF-κB-dependent signaling in sensory neurons [PMID:30033152, PMID:30976982].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing Fn14 as the sole physiological receptor for TWEAK resolved the identity of the cognate receptor-ligand pair and enabled all subsequent pathway studies.\",\n      \"evidence\": \"Receptor-ligand binding assays with recombinant proteins and cDNA transfection across multiple labs\",\n      \"pmids\": [\"12787562\", \"12821115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of the TWEAK–Fn14 complex not determined\", \"Whether additional co-receptors exist remained open\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstration that TWEAK/Fn14 activates NF-κB to drive proinflammatory chemokine production, and separately promotes proliferation while inhibiting differentiation in myoblasts, established Fn14 as a bifunctional mediator of inflammation and tissue remodeling.\",\n      \"evidence\": \"Fn14-KO mice plus pharmacological NF-κB inhibition in mesangial cells, bronchial epithelial cells, and myoblasts; in vivo muscle regeneration and colitis models\",\n      \"pmids\": [\"16424220\", \"15120617\", \"17124496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether canonical or non-canonical NF-κB mediates each cellular response was not yet resolved\", \"Signaling intermediates between Fn14 and IκB phosphorylation were uncharacterized\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery that Fn14 also engages PI3K/Akt and MAPK/ERK pathways in osteoblasts revealed that Fn14 signaling is not limited to NF-κB.\",\n      \"evidence\": \"Pharmacological pathway inhibitors and Fn14-Fc neutralization in MC3T3-E1 osteoblastic cells\",\n      \"pmids\": [\"16945157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PI3K/Akt and ERK act in parallel or sequentially downstream of Fn14 was not resolved\", \"Pathway engagement in primary osteoblasts not confirmed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Pharmacological (Fn14-Fc) and genetic (Fn14-KO) blockade in cerebral ischemia showed Fn14 controls blood-brain barrier integrity through NF-κB and MMP-9, establishing a pathogenic role in neuroinflammation.\",\n      \"evidence\": \"MCAO model with Fn14-Fc decoy and Fn14-KO mice; Evans blue extravasation, NF-κB/MMP-9 assays\",\n      \"pmids\": [\"16835630\", \"15681834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Fn14 expression on BBB endothelial cells versus perivascular cells was not definitively shown in vivo\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic and antibody-based TWEAK/Fn14 blockade in colitis models defined an epithelial TWEAK–Fn14 axis driving intestinal inflammation and injury.\",\n      \"evidence\": \"TWEAK-KO and Fn14-KO mice in TNBS colitis and irradiation models; anti-TWEAK mAb\",\n      \"pmids\": [\"19109961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of epithelial vs. immune cell Fn14 was not dissected with conditional KO\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that Fn14 self-associates via a Cys-122 disulfide in its cytoplasmic domain and can activate NF-κB without TWEAK binding revealed a ligand-independent signaling mode that explains overexpression-driven effects in tumors and injured tissue.\",\n      \"evidence\": \"Deletion mutagenesis, co-immunoprecipitation under non-reducing conditions, NF-κB reporter assay\",\n      \"pmids\": [\"23750247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts where TWEAK-independent signaling dominates remain uncharacterized\", \"Stoichiometry of self-associated Fn14 complexes not determined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that soluble TWEAK (trimeric) preferentially activates non-canonical NF-κB while membrane-bound TWEAK (higher-order) activates all pathways resolved how ligand valency differentially engages Fn14 signaling outputs.\",\n      \"evidence\": \"Comparison of soluble vs. membrane TWEAK and antibody oligomerization states with canonical/non-canonical NF-κB, IL-8, and cell death readouts\",\n      \"pmids\": [\"23532848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for valency-dependent signaling not established\", \"Whether endogenous TWEAK processing rate controls pathway balance in vivo is unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of RhoA/MRTF-A as a profibrotic Fn14 effector pathway in cardiac fibroblasts, complementing the established NF-κB axis, broadened the repertoire of Fn14 downstream signaling.\",\n      \"evidence\": \"Fn14-KO mice in pulmonary artery banding model; RhoA/MRTF-A pathway analysis in vitro\",\n      \"pmids\": [\"23325387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Fn14 activates RhoA (direct or indirect) is unknown\", \"Whether RhoA/MRTF-A contributes to fibrosis in non-cardiac tissues is untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstration of physical FGFR-1–Fn14 interaction and synergistic PI3K/Akt signaling in cardiomyocyte cell cycle reentry established Fn14 as a co-receptor capable of heterotypic receptor crosstalk beyond conventional TNF receptor signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, proximity ligation assay, kinase inhibitors, cell cycle assays in neonatal and adult cardiomyocytes\",\n      \"pmids\": [\"24571920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinant of FGFR-1/Fn14 interaction not mapped\", \"In vivo relevance for cardiac regeneration not shown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mechanistic dissection of Fn14 in muscle atrophy revealed activation of NF-κB, ubiquitin-proteasome, autophagy, caspase proteolysis, and PGC-1α suppression as a coordinated proteolytic and metabolic program, linking Fn14 to sarcopenia and muscle wasting.\",\n      \"evidence\": \"TWEAK-Tg, Fn14-KO, PGC-1α-Tg mice; denervation model; proteasome, autophagy, and fiber-type assays\",\n      \"pmids\": [\"24478779\", \"24327607\", \"24680686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Fn14 acts cell-autonomously in myofibers was not resolved with conditional KO\", \"Therapeutic window for Fn14 inhibition in atrophy not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of SMAD4 binding to the Fn14 promoter positioned Fn14 as a TGF-β transcriptional target driving fibroblast activation, while AR binding to the Fn14 enhancer suppresses expression, defining opposing transcriptional regulatory inputs.\",\n      \"evidence\": \"SMAD4 ChIP on Fn14 promoter; AR ChIP on Fn14 enhancer; siRNA and overexpression in fibroblasts and prostate cancer cells\",\n      \"pmids\": [\"26625141\", \"24970477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Integration of SMAD4 and AR regulation on the same promoter not tested\", \"Other transcription factors at the Fn14 locus remain poorly characterized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that visual experience induces Fn14 in thalamocortical neurons and that Fn14 is required for experience-dependent retinogeniculate refinement established a neuronal function for Fn14 beyond inflammation and tissue remodeling.\",\n      \"evidence\": \"Single-nucleus RNA-seq, Fn14-KO mice with visual deprivation paradigms, electrophysiology, anatomical tracing\",\n      \"pmids\": [\"30033152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling pathway in neurons (NF-κB or other) is not defined\", \"Whether TWEAK is the relevant ligand in this synaptic context is unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of TRAF3IP2 as a mediator linking Fn14 to p38 MAPK, NF-κB, and AP-1 in cardiac fibroblasts, with TRAF3IP2-KO mice protected from TWEAK-induced cardiac fibrosis, placed TRAF3IP2 as a proximal signaling adaptor.\",\n      \"evidence\": \"TRAF3IP2 siRNA and TRAF3IP2-KO mice; TWEAK infusion model; p38/NF-κB/AP-1 activation assays\",\n      \"pmids\": [\"29981796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRAF3IP2 binds Fn14 directly or through an intermediary TRAF is not shown\", \"Generalizability of TRAF3IP2 dependence to non-cardiac Fn14 signaling is untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstration that bile acids induce Fn14 via c-JUN and that TWEAK/Fn14 drives hepatocyte pyroptosis through NF-κB/Caspase-1/GSDMD added pyroptosis to the Fn14 cell death repertoire and identified a cholestasis-specific transcriptional input.\",\n      \"evidence\": \"Tnfrsf12a-KO mice in BDL and DDC models; c-JUN ChIP; pyroptosis markers (NLRP3, cleaved Caspase-1, GSDMD); CRISPR\",\n      \"pmids\": [\"36690641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Fn14 activates NLRP3 directly or through NF-κB-dependent transcriptional priming is not fully resolved\", \"Relevance beyond murine cholestasis models not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Pharmacological FN14 antagonism reduced ductular reactions and biliary fibrosis driven by hepatic progenitor cells via non-canonical NF-κB, demonstrating Fn14 as a druggable target in biliary disease and linking it to progenitor cell biology.\",\n      \"evidence\": \"FN14 antagonist L524-0366 in RRV biliary atresia model; HPC organoid culture; non-canonical NF-κB and RNA-seq\",\n      \"pmids\": [\"36626628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity and pharmacokinetics of L524-0366 not fully characterized\", \"Whether progenitor cell Fn14 function extends to other liver injury contexts is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of TWEAK–Fn14 interaction and how receptor clustering geometry dictates canonical vs. non-canonical NF-κB selectivity remain unresolved; conditional knockout studies have not dissected cell-type-autonomous Fn14 functions in most tissues; the mechanism by which Fn14 activates RhoA, the identity of neuronal Fn14 signaling partners, and the full spectrum of Fn14 adaptors beyond TRAF and TRAF3IP2 are open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of TWEAK–Fn14 complex\", \"Conditional knockout studies lacking for most tissues\", \"Neuronal Fn14 signaling mechanism undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2, 5, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [25, 34]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 13, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 7, 16, 25, 34, 36, 37, 40]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 8, 19, 20, 39]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 11, 12, 40]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [10, 37]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [14, 17, 31, 34, 35]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TNFSF12\",\n      \"FGFR1\",\n      \"TRAF3IP2\",\n      \"NFKB1\",\n      \"RELA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}