Affinage

TNFRSF12A

Tumor necrosis factor receptor superfamily member 12A · UniProt Q9NP84

Length
129 aa
Mass
13.9 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    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

    PMID:12787562 PMID:12821115

    Open questions at the time
    • Crystal structure of the TWEAK–Fn14 complex not determined
    • Whether additional co-receptors exist remained open
  2. 2006 High

    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

    PMID:15120617 PMID:16424220 PMID:17124496

    Open questions at the time
    • Whether canonical or non-canonical NF-κB mediates each cellular response was not yet resolved
    • Signaling intermediates between Fn14 and IκB phosphorylation were uncharacterized
  3. 2006 Medium

    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

    PMID:16945157

    Open questions at the time
    • Whether PI3K/Akt and ERK act in parallel or sequentially downstream of Fn14 was not resolved
    • Pathway engagement in primary osteoblasts not confirmed
  4. 2006 High

    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

    PMID:15681834 PMID:16835630

    Open questions at the time
    • Direct Fn14 expression on BBB endothelial cells versus perivascular cells was not definitively shown in vivo
  5. 2008 High

    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

    PMID:19109961

    Open questions at the time
    • Relative contribution of epithelial vs. immune cell Fn14 was not dissected with conditional KO
  6. 2013 High

    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

    PMID:23750247

    Open questions at the time
    • Physiological contexts where TWEAK-independent signaling dominates remain uncharacterized
    • Stoichiometry of self-associated Fn14 complexes not determined
  7. 2013 High

    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

    PMID:23532848

    Open questions at the time
    • Structural basis for valency-dependent signaling not established
    • Whether endogenous TWEAK processing rate controls pathway balance in vivo is unknown
  8. 2013 High

    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

    PMID:23325387

    Open questions at the time
    • How Fn14 activates RhoA (direct or indirect) is unknown
    • Whether RhoA/MRTF-A contributes to fibrosis in non-cardiac tissues is untested
  9. 2014 High

    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

    PMID:24571920

    Open questions at the time
    • Structural determinant of FGFR-1/Fn14 interaction not mapped
    • In vivo relevance for cardiac regeneration not shown
  10. 2014 High

    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

    PMID:24327607 PMID:24478779 PMID:24680686

    Open questions at the time
    • Whether Fn14 acts cell-autonomously in myofibers was not resolved with conditional KO
    • Therapeutic window for Fn14 inhibition in atrophy not defined
  11. 2015 Medium

    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

    PMID:24970477 PMID:26625141

    Open questions at the time
    • Integration of SMAD4 and AR regulation on the same promoter not tested
    • Other transcription factors at the Fn14 locus remain poorly characterized
  12. 2018 High

    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

    PMID:30033152

    Open questions at the time
    • Downstream signaling pathway in neurons (NF-κB or other) is not defined
    • Whether TWEAK is the relevant ligand in this synaptic context is unknown
  13. 2018 High

    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

    PMID:29981796

    Open questions at the time
    • Whether TRAF3IP2 binds Fn14 directly or through an intermediary TRAF is not shown
    • Generalizability of TRAF3IP2 dependence to non-cardiac Fn14 signaling is untested
  14. 2021 High

    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

    PMID:36690641

    Open questions at the time
    • Whether Fn14 activates NLRP3 directly or through NF-κB-dependent transcriptional priming is not fully resolved
    • Relevance beyond murine cholestasis models not tested
  15. 2023 Medium

    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

    PMID:36626628

    Open questions at the time
    • Selectivity and pharmacokinetics of L524-0366 not fully characterized
    • Whether progenitor cell Fn14 function extends to other liver injury contexts is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No crystal or cryo-EM structure of TWEAK–Fn14 complex
  • Conditional knockout studies lacking for most tissues
  • Neuronal Fn14 signaling mechanism undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1474244 Extracellular matrix organization 5 R-HSA-168256 Immune System 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1500931 Cell-Cell communication 2
Partners
FGFR1NFKB1RELATNFSF12TRAF3IP2

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. Receptor-ligand binding assays, cDNA transfection, recombinant protein characterization Cytokine & growth factor reviews High 12787562
2003 Murine TWEAK binds to murine Fn14 transfectants and induces cell death; macrophages secrete functional soluble TWEAK; Fn14 overexpression confers sensitivity to TWEAK-induced cytotoxicity. cDNA transfection, monoclonal antibody generation, cell death assay, functional neutralization Biochemical and biophysical research communications Medium 12821115
2004 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. Cell stimulation assay, blocking antibody, IκBα phosphorylation assay, NF-κB inhibitor (BAY11-7082) Biochemical and biophysical research communications Medium 15120617
2005 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. Murine MCAO model, intracerebroventricular injection of Fn14-Fc decoy receptor, histopathology, ELISA The American journal of pathology Medium 15681834
2006 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. Murine MCAO model, Fn14-Fc decoy receptor, Fn14 knockout mice, Evans blue dye extravasation, NF-κB/MMP-9 assays Journal of cerebral blood flow and metabolism High 16835630
2006 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. Cell stimulation, IκB phosphorylation assay, NF-κB inhibitor, Fn14-KO cells and mice, ELISA Journal of immunology High 16424220
2006 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. In vitro myoblast culture, Fn14-KO mouse generation, NF-κB activation assay, cardiotoxin-injection regeneration model, histology The EMBO journal High 17124496
2006 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. Cell stimulation, pathway inhibitors, osteoblast differentiation markers, Fn14-Fc chimera neutralization Arthritis research & therapy Medium 16945157
2008 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. TNBS colitis model, TWEAK-KO and Fn14-KO mice, anti-TWEAK mAb, gene expression profiling, gamma-irradiation injury model Gastroenterology High 19109961
2009 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. ApoE-/- mouse model, Fn14-Fc treatment, plaque morphometry, in vitro macrophage lipid uptake assay Arteriosclerosis, thrombosis, and vascular biology Medium 19762780
2011 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. In vitro BBB model (HCMEC cultures), TWEAK stimulation, cytokine ELISA, MMP assay, permeability assay Journal of neuroinflammation Medium 23320797
2011 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. Intestinal explant cultures from TWEAK-KO mice, caspase-3 activation assay, ADAM17 inhibition, gene expression profiling Gastroenterology High 21893119
2011 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. Fn14 signaling assay, in vitro apoptosis assay, multiple xenograft models, valency manipulation, Fc variant comparison mAbs Medium 21697654
2011 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. Confocal microscopy internalization assay, cytotoxicity assay, apoptosis detection, xenograft tumor model Molecular cancer therapeutics Medium 21586630
2012 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. Neonatal rat cardiac fibroblast culture, siRNA knockdown of Fn14, NF-κB activation assay, MMP-9 measurement, collagen synthesis assay Molecular biology reports Medium 22555979
2013 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. Deletion mutagenesis, co-immunoprecipitation, SDS-PAGE under non-reducing conditions, NF-κB reporter assay, transfection PloS one High 23750247
2013 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. NFκB pathway analysis (p100 processing, classical NF-κB), IL-8 ELISA, cell death assay, protein G oligomerization, FcγR-binding, soluble vs. membrane TWEAK comparison The Journal of biological chemistry High 23532848
2013 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. Fn14-KO mice (PAB model), cell culture RhoA/MRTF-A pathway analysis, fibroblast proliferation/differentiation assay, endothelin-1 treatment Basic research in cardiology High 23325387
2013 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. TWEAK-Tg mice, Fn14-KO mice, TWEAK-KO mice, PGC-1α transgenic mice, denervation model, NF-κB activity assay, gene expression analysis FASEB journal High 24327607
2013 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. Fn14-KO mice (chronic colitis model), TSLP receptor-KO mice, colon explant TSLP assay, fibroblast proliferation assay Mucosal immunology High 23462911
2013 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. Podocyte cell culture, NFκB inhibitor, Fn14-KO mice (protein overload proteinuria model), adenovirus-mediated TWEAK overexpression in mice, macrophage infiltration assay Biochimica et biophysica acta High 23999007
2014 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. NF-κB pathway analysis (canonical vs. non-canonical), cIAP1 characterization, myoblast proliferation/differentiation/fusion assays Frontiers in immunology Medium 24550918
2014 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. 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 Cancer research Medium 24970477
2014 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. Cyclic stretch assay, ROS measurement, kinase pathway inhibitors, JNK/p38/ERK activation assays, Fn14 expression measurement, apoptosis assay The Journal of biological chemistry Medium 24446436
2014 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. 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 Frontiers in immunology High 24478779
2014 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. Co-immunoprecipitation, proximity ligation assay, kinase inhibitors, Fn14 overexpression, cell cycle reentry assay in neonatal and adult cardiomyocytes, PI3K/Akt inhibition FASEB journal High 24571920
2014 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. TWEAK stimulation, NF-κB activation assay, Mcl-1 siRNA, pharmacological Mcl-1 inhibitor (EU-5148), cisplatin/radiation survival assay Molecular cancer research Medium 24469836
2014 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. Fn14-KO mice in RNA toxicity model, anti-TWEAK antibody treatment, NF-κB signaling assay, muscle histopathology, functional outcome measures Human molecular genetics Medium 25504044
2014 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. Fn14-KO mice (aging model), NF-κB DNA-binding assay, ubiquitin/autophagy markers, fiber morphometry, histology Biochemical and biophysical research communications Medium 24680686
2014 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. Human skeletal muscle biopsies, gene and protein expression time course, alternative NF-κB pathway markers Journal of applied physiology Medium 25539934
2015 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. Fn14-KO and TWEAK-KO host mice, anti-Fn14 antibodies, tumor implantation models, body composition analysis, survival studies Cell High 26359988
2015 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. SMAD4 ChIP on Fn14 promoter, Fn14 siRNA, Fn14 overexpression, ECM/collagen gene expression assay in dermal fibroblasts PloS one Medium 26625141
2016 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. Fn14-KO mice (DSS colitis and AOM/DSS tumor model), bone marrow chimera experiments, endoscopic and histological scoring Cancer research Medium 27634763
2018 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. Single-nucleus RNA sequencing, electrophysiology, structural (retinogeniculate input) analysis, Fn14-KO mice (visual deprivation/experience paradigms) Neuron High 30033152
2018 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. TRAF3IP2 siRNA, TRAF3IP2-KO mice, TWEAK infusion model, p38/NF-κB/AP-1 activation assay, collagen assay, migration assay Journal of molecular and cellular cardiology High 29981796
2018 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. Fn14-KO BALB/c mice (burn wound model), TWEAK stimulation of HUVEC/fibroblasts, Fn14 siRNA, cytokine measurement, α-SMA immunostaining The Journal of investigative dermatology Medium 30081003
2018 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). HL-1 atrial myocyte culture, TWEAK stimulation, Fn14 siRNA, JAK2/STAT3 siRNA, hypertrophy marker expression Journal of cellular and molecular medicine Medium 29971943
2019 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. 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 EBioMedicine High 31395500
2019 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. Spinal nerve ligation model, Fn14 siRNA (intrathecal), Fn14 overexpression, p65 nuclear translocation assay, pain behavior assays Molecular neurobiology Medium 30976982
2020 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. Flow cytometry, conditioned medium macrophage polarization assay, Fn14-KO mice (TAA CCA model), TWEAK overexpression, CCA xenograft + MCP-1 blockade, proteomics Journal of hepatology High 33221352
2021 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. 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 Cell death discovery High 36690641
2023 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. RRV mouse model of biliary atresia, FN14 antagonist (L524-0366), murine HPC organoid culture, non-canonical NF-κB signaling assay, RNA-seq analysis Hepatology Medium 36626628

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting. Nature reviews. Drug discovery 492 18404150
2003 TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that binds the TweakR/Fn14 receptor. Cytokine & growth factor reviews 253 12787562
2007 TWEAKing tissue remodeling by a multifunctional cytokine: role of TWEAK/Fn14 pathway in health and disease. Cytokine 244 17981048
2006 TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration. The EMBO journal 192 17124496
2011 TWEAK/Fn14 pathway: an immunological switch for shaping tissue responses. Immunological reviews 180 22017434
2006 Proinflammatory effects of TWEAK/Fn14 interactions in glomerular mesangial cells. Journal of immunology (Baltimore, Md. : 1950) 139 16424220
2015 Targeting of Fn14 Prevents Cancer-Induced Cachexia and Prolongs Survival. Cell 128 26359988
2005 A soluble Fn14-Fc decoy receptor reduces infarct volume in a murine model of cerebral ischemia. The American journal of pathology 114 15681834
2004 The role of TWEAK/Fn14 in the pathogenesis of inflammation and systemic autoimmunity. Frontiers in bioscience : a journal and virtual library 97 15353286
2012 Inhibition of the TWEAK/Fn14 pathway attenuates renal disease in nephrotoxic serum nephritis. Clinical immunology (Orlando, Fla.) 86 22982296
2013 Neuropsychiatric Lupus, the Blood Brain Barrier, and the TWEAK/Fn14 Pathway. Frontiers in immunology 80 24400009
2006 TWEAK-Fn14 pathway inhibition protects the integrity of the neurovascular unit during cerebral ischemia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 80 16835630
2013 The TWEAK-Fn14 system as a potential drug target. British journal of pharmacology 74 23957828
2011 Interleukin-13 damages intestinal mucosa via TWEAK and Fn14 in mice-a pathway associated with ulcerative colitis. Gastroenterology 74 21893119
2012 ALKBH3 contributes to survival and angiogenesis of human urothelial carcinoma cells through NADPH oxidase and tweak/Fn14/VEGF signals. Clinical cancer research : an official journal of the American Association for Cancer Research 67 22850567
2013 Deletion of Fn14 receptor protects from right heart fibrosis and dysfunction. Basic research in cardiology 66 23325387
2013 TWEAK/Fn14 pathway modulates properties of a human microvascular endothelial cell model of blood brain barrier. Journal of neuroinflammation 64 23320797
2004 TWEAK/Fn14 interaction stimulates human bronchial epithelial cells to produce IL-8 and GM-CSF. Biochemical and biophysical research communications 64 15120617
2008 TWEAK/Fn14 pathway: a nonredundant role in intestinal damage in mice through a TWEAK/intestinal epithelial cell axis. Gastroenterology 63 19109961
2015 The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics. Oncogene 62 26300004
2006 TWEAK/Fn14 interaction regulates RANTES production, BMP-2-induced differentiation, and RANKL expression in mouse osteoblastic MC3T3-E1 cells. Arthritis research & therapy 61 16945157
2014 TWEAK/Fn14 Signaling Axis Mediates Skeletal Muscle Atrophy and Metabolic Dysfunction. Frontiers in immunology 60 24478779
2013 Regulatory circuitry of TWEAK-Fn14 system and PGC-1α in skeletal muscle atrophy program. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 59 24327607
2013 The TWEAK-Fn14 pathway: a potent regulator of skeletal muscle biology in health and disease. Cytokine & growth factor reviews 58 24444596
2011 Development and characterization of a potent immunoconjugate targeting the Fn14 receptor on solid tumor cells. Molecular cancer therapeutics 58 21586630
2008 No end in site: TWEAK/Fn14 activation and autoimmunity associated- end-organ pathologies. Journal of leukocyte biology 58 18483204
2006 TWEAK and Fn14: new molecular targets for cancer therapy? Cancer letters 57 15885893
2012 The TWEAK/Fn14 pathway as an aggravating and perpetuating factor in inflammatory diseases: focus on inflammatory bowel diseases. Journal of leukocyte biology 56 22672874
2021 The TWEAK/Fn14/CD163 axis-implications for metabolic disease. Reviews in endocrine & metabolic disorders 55 34542797
2020 TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression. Journal of hepatology 55 33221352
2017 TWEAK/Fn14 signaling in tumors. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 55 28639899
2018 Visual Experience-Dependent Expression of Fn14 Is Required for Retinogeniculate Refinement. Neuron 53 30033152
2012 TWEAK/Fn14 promotes the proliferation and collagen synthesis of rat cardiac fibroblasts via the NF-кB pathway. Molecular biology reports 52 22555979
2013 TWEAK/Fn14 and Non-Canonical NF-kappaB Signaling in Kidney Disease. Frontiers in immunology 51 24339827
2007 Identification of Fn14/TWEAK receptor as a potential therapeutic target in esophageal adenocarcinoma. International journal of cancer 51 17594693
2003 Characterization of murine TWEAK and its receptor (Fn14) by monoclonal antibodies. Biochemical and biophysical research communications 51 12821115
2017 Regulation of Fn14 Receptor and NF-κB Underlies Inflammation in Meniere's Disease. Frontiers in immunology 50 29326686
2017 TWEAK/Fn14 Activation Participates in Skin Inflammation. Mediators of inflammation 49 29038621
2008 Induction of the cytokine TWEAK and its receptor Fn14 in ischemic stroke. Journal of the neurological sciences 49 18793781
2014 AR-regulated TWEAK-FN14 pathway promotes prostate cancer bone metastasis. Cancer research 48 24970477
2007 Role of TWEAK and Fn14 in tumor biology. Frontiers in bioscience : a journal and virtual library 48 17127278
2009 Fn14-Fc fusion protein regulates atherosclerosis in ApoE-/- mice and inhibits macrophage lipid uptake in vitro. Arteriosclerosis, thrombosis, and vascular biology 47 19762780
2007 TWEAK and Fn14. New players in the pathogenesis of atherosclerosis. Frontiers in bioscience : a journal and virtual library 45 17485328
2013 Fn14 in podocytes and proteinuric kidney disease. Biochimica et biophysica acta 44 23999007
2014 Role of the TWEAK-Fn14-cIAP1-NF-κB Signaling Axis in the Regulation of Myogenesis and Muscle Homeostasis. Frontiers in immunology 43 24550918
2008 Involvement of TWEAK/Fn14 interaction in the synovial inflammation of RA. Rheumatology (Oxford, England) 43 18310134
2010 TWEAK/Fn14 promotes apoptosis of human endometrial cancer cells via caspase pathway. Cancer letters 41 20189297
2020 Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK)/Fibroblast Growth Factor-Inducible 14 (Fn14) Axis in Cardiovascular Diseases: Progress and Challenges. Cells 40 32053869
2011 Development of an Fn14 agonistic antibody as an anti-tumor agent. mAbs 40 21697654
2010 Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 during cardiac remodelling in rats. Acta physiologica (Oxford, England) 40 20082609
2020 TWEAK/Fn14 axis is an important player in fibrosis. Journal of cellular physiology 39 33000480
2013 TWEAK-independent Fn14 self-association and NF-κB activation is mediated by the C-terminal region of the Fn14 cytoplasmic domain. PloS one 39 23750247
2018 The TNF receptor family member Fn14 is highly expressed in recurrent glioblastoma and in GBM patient-derived xenografts with acquired temozolomide resistance. Neuro-oncology 38 29897522
2013 Fibroblast growth factor inducible (Fn14)-specific antibodies concomitantly display signaling pathway-specific agonistic and antagonistic activity. The Journal of biological chemistry 38 23532848
2012 The TWEAK-Fn14 system: breaking the silence of cytokine-induced skeletal muscle wasting. Current molecular medicine 38 22082477
2014 TWEAK-Fn14 pathway activation after exercise in human skeletal muscle: insights from two exercise modes and a time course investigation. Journal of applied physiology (Bethesda, Md. : 1985) 37 25539934
2013 TWEAK/Fn14 pathway promotes a T helper 2-type chronic colitis with fibrosis in mice. Mucosal immunology 37 23462911
2014 Mcl-1 mediates TWEAK/Fn14-induced non-small cell lung cancer survival and therapeutic response. Molecular cancer research : MCR 36 24469836
2014 The expression of Fn14 via mechanical stress-activated JNK contributes to apoptosis induction in osteoblasts. The Journal of biological chemistry 35 24446436
2018 TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cultured cardiac fibroblasts and the heart. Journal of molecular and cellular cardiology 34 29981796
2018 Tnfrsf12a-Mediated Atherosclerosis Signaling and Inflammatory Response as a Common Protection Mechanism of Shuxuening Injection Against Both Myocardial and Cerebral Ischemia-Reperfusion Injuries. Frontiers in pharmacology 33 29681850
2014 TWEAK-Fn14 Cytokine-Receptor Axis: A New Player of Myocardial Remodeling and Cardiac Failure. Frontiers in immunology 33 24611063
2018 TWEAK/Fn14 Signals Mediate Burn Wound Repair. The Journal of investigative dermatology 32 30081003
2016 Role of the TWEAK/Fn14 pathway in autoimmune diseases. Immunologic research 32 26659091
2014 TWEAK/Fn14, a pathway and novel therapeutic target in myotonic dystrophy. Human molecular genetics 32 25504044
2023 Hepatic TNFRSF12A promotes bile acid-induced hepatocyte pyroptosis through NFκB/Caspase-1/GSDMD signaling in cholestasis. Cell death discovery 31 36690641
2017 Regulation of Neuroinflammation: What Role for the Tumor Necrosis Factor-Like Weak Inducer of Apoptosis/Fn14 Pathway? Frontiers in immunology 31 29201025
2020 TWEAK/Fn14 axis in respiratory diseases. Clinica chimica acta; international journal of clinical chemistry 30 32526219
2019 A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis. EBioMedicine 30 31395500
2016 Out of the TWEAKlight: Elucidating the Role of Fn14 and TWEAK in Acute Kidney Injury. Seminars in nephrology 30 27339384
2013 BAFF, APRIL, TWEAK, BCMA, TACI and Fn14 proteins are related to human glioma tumor grade: immunohistochemistry and public microarray data meta-analysis. PloS one 30 24376672
2013 Antitumor activity of a humanized, bivalent immunotoxin targeting fn14-positive solid tumors. Cancer research 29 23722548
2021 Interruption of neutrophil extracellular traps formation dictates host defense and tubular HOXA5 stability to augment efficacy of anti-Fn14 therapy against septic AKI. Theranostics 28 34646379
2013 TWEAK/Fn14 signaling mediates gastric cancer cell resistance to 5-fluorouracil via NF-κB activation. International journal of oncology 28 24337061
2012 Expression of TweakR in breast cancer and preclinical activity of enavatuzumab, a humanized anti-TweakR mAb. Journal of cancer research and clinical oncology 28 23073510
2014 TWEAK/Fn14 pathway is a novel mediator of retinal neovascularization. Investigative ophthalmology & visual science 27 24408972
2020 Controversies in TWEAK-Fn14 signaling in skeletal muscle atrophy and regeneration. Cellular and molecular life sciences : CMLS 26 32200423
2018 TWEAK/Fn14 interaction induces proliferation and migration in human airway smooth muscle cells via activating the NF-κB pathway. Journal of cellular biochemistry 26 29143982
2014 FGF1-mediated cardiomyocyte cell cycle reentry depends on the interaction of FGFR-1 and Fn14. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 24571920
2013 TWEAK and Fn14 in the Neurovascular Unit. Frontiers in immunology 26 24273541
2021 Fn14-targeted BiTE and CAR-T cells demonstrate potent preclinical activity against glioblastoma. Oncoimmunology 25 34595061
2015 Fn14, a Downstream Target of the TGF-β Signaling Pathway, Regulates Fibroblast Activation. PloS one 25 26625141
2021 TWEAK-Fn14 as a common pathway in the heart and the kidneys in cardiorenal syndrome. The Journal of pathology 24 33512736
2018 TWEAK/Fn14 mediates atrial-derived HL-1 myocytes hypertrophy via JAK2/STAT3 signalling pathway. Journal of cellular and molecular medicine 24 29971943
2016 Protective Role for TWEAK/Fn14 in Regulating Acute Intestinal Inflammation and Colitis-Associated Tumorigenesis. Cancer research 24 27634763
2014 A novel llama antibody targeting Fn14 exhibits anti-metastatic activity in vivo. mAbs 24 24135629
2014 The TWEAK-Fn14 dyad is involved in age-associated pathological changes in skeletal muscle. Biochemical and biophysical research communications 24 24680686
2014 Development of human serine protease-based therapeutics targeting Fn14 and identification of Fn14 as a new target overexpressed in TNBC. Molecular cancer therapeutics 23 25239934
2012 A Bioinformatics Resource for TWEAK-Fn14 Signaling Pathway. Journal of signal transduction 23 22649723
2010 Therapeutic potential of the TWEAK/Fn14 pathway in intractable gastrointestinal cancer. Experimental and therapeutic medicine 23 22977477
2007 Tweak and FN14 in central nervous system health and disease. Frontiers in bioscience : a journal and virtual library 23 17485258
2016 Soluble Fn14 Is Detected and Elevated in Mouse and Human Kidney Disease. PloS one 22 27171494
2016 Correlation of EGFR Del 19 with Fn14/JAK/STAT signaling molecules in non-small cell lung cancer. Oncology reports 22 27350337
2023 TWEAK/FN14 promotes profibrogenic pathway activation in Prominin-1-expressing hepatic progenitor cells in biliary atresia. Hepatology (Baltimore, Md.) 21 36626628
2013 Expression of TWEAK/Fn14 in neuroblastoma: implications in tumorigenesis. International journal of oncology 21 23443741
2021 Empagliflozin Disrupts a Tnfrsf12a-Mediated Feed Forward Loop That Promotes Left Ventricular Hypertrophy. Cardiovascular drugs and therapy 20 33886003
2019 Fn14 Participates in Neuropathic Pain Through NF-κB Pathway in Primary Sensory Neurons. Molecular neurobiology 20 30976982
2018 The TWEAK/Fn14 pathway is required for calcineurin inhibitor toxicity of the kidneys. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20 29266762
2018 TWEAK/Fn14 Interaction Confers Aggressive Properties to Cutaneous Squamous Cell Carcinoma. The Journal of investigative dermatology 20 30414907
2017 TWEAK/Fn14 promotes oxidative stress through AMPK/PGC‑1α/MnSOD signaling pathway in endothelial cells. Molecular medicine reports 20 29257217