Affinage

TNFRSF12A

Tumor necrosis factor receptor superfamily member 12A · UniProt Q9NP84

Length
129 aa
Mass
13.9 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFRSF12A (Fn14) is the cognate receptor for the TNF-family ligand TWEAK and the smallest TNFR superfamily member, signaling through recruitment of TRAFs to drive predominantly NF-κB-based transcriptional responses in a highly cell-context-dependent manner (PMID:12787562). Ligand engagement activates canonical and non-canonical NF-κB, with soluble TWEAK and receptor dimerization preferentially triggering the alternative pathway while membrane-bound TWEAK (or oligomerized agonist antibodies) engages the full repertoire of Fn14 signaling (PMID:23532848); Fn14 can additionally self-associate via an intermolecular disulfide bond at Cys122 to activate NF-κB independently of TWEAK (PMID:23750247). Downstream, Fn14 couples to fibrogenic and inflammatory programs through RhoA-dependent MRTF-A nuclear translocation and collagen induction (PMID:23325387), the TRAF3IP2 adaptor driving p38/NF-κB/AP-1 activation (PMID:29981796), and JAK2/STAT3 signaling (PMID:29971943), and it physically interacts with FGFR-1 to synergize in PI3K/Akt-driven cardiomyocyte cell cycle reentry (PMID:24571920). Fn14 expression is itself a highly inducible node, upregulated by mechanical stress via RhoA/ROCK (PMID:19629561), growth factor and cytokine cues (PMID:19629561, PMID:24710956), and bile acid-driven c-JUN binding (PMID:36690641), and repressed by androgen receptor (PMID:24970477) and ThPOK at the promoter (PMID:34353698). Physiologically and pathologically, Fn14 mediates experience-dependent retinogeniculate synaptic refinement (PMID:30033152), myoblast fusion via Wnt/calcium signaling (PMID:37813488), cardiac and biliary fibrosis (PMID:23325387, PMID:36626628), hepatocyte cell death (RIPK1-dependent apoptosis and NF-κB/Caspase-1/GSDMD pyroptosis) (PMID:36690641, PMID:35853848), tumor-cell-autonomous cancer cachexia (PMID:26359988), and super-enhancer-driven NAMPT metabolic reprogramming for breast cancer metastasis (PMID:38965263), while conversely restraining fibroblast activation and supporting pro-regenerative macrophage recruitment in the lung (PMID:39827460).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2003 High

    Established the receptor identity of Fn14, answering what receptor transduces TWEAK signals and how it couples to downstream effectors.

    Evidence Receptor-ligand binding assays and transfection studies identifying Fn14 as the cognate TWEAK receptor signaling via TRAFs

    PMID:12787562

    Open questions at the time
    • Did not define which TRAF members are recruited or the structural basis of recruitment
    • Did not resolve whether a second TWEAK receptor exists
  2. 2003 Medium

    Showed Fn14 engagement can produce divergent outputs (NF-κB/JNK vs. weak MAPK) and that some TWEAK effects are Fn14-independent, raising the possibility of a second receptor.

    Evidence Flow cytometry, neutralizing antibodies, and signaling pathway analysis in HT-29 and RAW264.7 cells; cytotoxicity assays in Fn14-transfected cells

    PMID:12794080 PMID:12821115

    Open questions at the time
    • The proposed second TWEAK receptor (TweakR2) was never molecularly identified
    • Context-dependence of NF-κB vs. MAPK output not mechanistically resolved
  3. 2009 Medium

    Defined Fn14 as a mechanically and humorally inducible receptor, answering how its expression is controlled upstream of TWEAK responsiveness.

    Evidence siRNA and pharmacological RhoA/ROCK inhibition in neonatal rat cardiomyocytes with NF-κB readouts

    PMID:19629561

    Open questions at the time
    • Did not identify the transcription factors executing RhoA/ROCK-dependent Fn14 induction
    • Restricted to cardiomyocyte context
  4. 2013 High

    Resolved how Fn14 drives fibrosis by linking it to a RhoA/MRTF-A/collagen transcriptional axis and demonstrating a causal role in cardiac remodeling.

    Evidence Fn14 knockout mice with pulmonary artery banding plus in vitro fibroblast activation and MRTF-A pathway analysis

    PMID:23325387

    Open questions at the time
    • Did not define how Fn14 mechanistically activates RhoA
    • Cross-talk with NF-κB fibrotic outputs not delineated
  5. 2013 High

    Demonstrated TWEAK-independent signaling, answering whether Fn14 oligomerization alone is sufficient for activity and identifying Cys122 disulfide-mediated dimerization as the mechanism.

    Evidence Deletion and site-directed mutagenesis (Cys122), non-reducing SDS-PAGE, and NF-κB reporter assays

    PMID:23750247

    Open questions at the time
    • Physiological relevance of self-association at endogenous expression levels not established
    • Did not test which signaling branches require dimerization vs. ligand
  6. 2013 High

    Dissected signaling thresholds, showing dimerization triggers alternative NF-κB while higher-order clustering (membrane TWEAK or oligomerized antibody) engages all pathways.

    Evidence NF-κB reporters, IL-8 ELISA, cell death assays, and antibody oligomerization via protein G/FcγR cross-linking

    PMID:23532848

    Open questions at the time
    • Structural basis distinguishing dimer vs. higher-order signaling not resolved
    • TRAF-level mechanism of canonical vs. non-canonical selection not defined
  7. 2014 High

    Identified a direct Fn14–FGFR-1 physical interaction, answering how Fn14 can promote cardiomyocyte proliferation via PI3K/Akt cross-talk with growth factor receptors.

    Evidence Co-immunoprecipitation, proximity ligation assay, and cell cycle epistasis with PI3K/Akt analysis

    PMID:24571920

    Open questions at the time
    • Structural interface of the Fn14–FGFR-1 complex unknown
    • Generality beyond cardiomyocytes not tested
  8. 2014 High

    Mapped multiple upstream regulators and disease contexts, establishing Fn14 induction by mechanical stretch, MET, and NFAT1, repression by AR, and roles in bone metastasis and muscle disease.

    Evidence Cyclic stretch with ASK1-JNK analysis (osteoblasts), HGF/MET and NFAT1 manipulation in cancer, ChIP and IKKβ reconstitution in bone metastasis, and knockout/anti-TWEAK rescue in a myotonic dystrophy model

    PMID:22767506 PMID:24446436 PMID:24710956 PMID:24970477 PMID:25504044

    Open questions at the time
    • Context-specific reasons Fn14 is anti-invasive in some settings and pro-metastatic in others unresolved
    • How distinct transcription factors converge on the Fn14 locus not integrated
  9. 2015 High

    Localized the cachexia-driving Fn14 to tumor cells rather than host tissue, answering the cell-autonomy of Fn14 in cancer-induced wasting.

    Evidence Tumor transplantation into Fn14- and TWEAK-knockout hosts plus anti-Fn14 antibody intervention with body composition analysis

    PMID:26359988

    Open questions at the time
    • The tumor-derived factors downstream of Fn14 that drive wasting not fully defined
    • Whether host TWEAK or autocrine ligand engages tumor Fn14 unresolved
  10. 2017 Medium

    Extended Fn14 inflammatory signaling to hepatic stellate cells, showing NF-κB/STAT3 cooperation amplifies cytokine output.

    Evidence siRNA knockdown, pathway Western blotting, and Co-IP of NF-κB/STAT3 in LX-2 cells

    PMID:28411440

    Open questions at the time
    • Direct physical NF-κB/STAT3 interaction not validated reciprocally in vivo
    • In vivo relevance to liver fibrosis not shown in this study
  11. 2018 High

    Identified discrete downstream effectors (TRAF3IP2, JAK2/STAT3, ADAM17) and established a physiological CNS role, broadening the mechanistic and functional repertoire of Fn14.

    Evidence TRAF3IP2 knockout and siNA epistasis in cardiac fibroblasts, JAK2/STAT3 siRNA in atrial myocytes, ADAM17 siRNA in keratinocytes, and single-nucleus RNA-seq with knockout electrophysiology in dLGN neurons

    PMID:28351660 PMID:29971943 PMID:29981796 PMID:30033152

    Open questions at the time
    • How the same receptor selects TRAF3IP2 vs. JAK2/STAT3 vs. ADAM17 branches per tissue is unclear
    • Synaptic refinement effector mechanism downstream of Fn14 undefined
  12. 2019 Medium

    Showed Fn14 is sufficient and necessary for injury-induced pain via NF-κB activation in sensory neurons.

    Evidence Spinal nerve ligation model with Fn14 gain- and loss-of-function and p65 nuclear translocation plus behavioral testing

    PMID:30976982

    Open questions at the time
    • Ligand source driving neuronal Fn14 activation not identified
    • Downstream pain-relevant NF-κB targets not defined
  13. 2021 Medium

    Established ThPOK as a direct transcriptional repressor of TNFRSF12A, complementing earlier AR-mediated repression in defining the regulatory architecture of the locus.

    Evidence ChIP, luciferase reporter, and siRNA in gastric cancer cells with T cell co-culture

    PMID:34353698

    Open questions at the time
    • Interplay between activating (c-JUN, NFAT1) and repressive (ThPOK, AR) inputs at the promoter not integrated
    • Mechanism of T cell regulation downstream of Fn14 not defined
  14. 2022 Medium

    Distinguished the hepatocyte cell-death mode driven by Fn14 as RIPK1-dependent apoptosis, refining how Fn14 kills cells in acute liver failure.

    Evidence TWEAK/Tnfrsf12a inhibition in TAA and APAP mouse models with pathway discrimination from necroptosis/pyroptosis and human biopsy validation

    PMID:35853848

    Open questions at the time
    • Why hepatocytes use RIPK1-apoptosis vs. pyroptosis in different injuries unresolved
    • Direct molecular link from Fn14 to RIPK1 not defined
  15. 2023 High

    Resolved a bile-acid/c-JUN-induced pyroptotic Fn14 program and a profibrogenic hepatic progenitor program, while a myoblast study placed Fn14 upstream of Wnt/calcium signaling in muscle fusion.

    Evidence Tnfrsf12a knockout cholestasis models with ChIP and Caspase-1/GSDMD analysis, Fn14 antagonism in a biliary atresia model with organoids, and conditional myoblast knockout with Wnt rescue

    PMID:36626628 PMID:36690641 PMID:37813488

    Open questions at the time
    • How Fn14 mechanistically engages the Wnt/calcium axis in myoblasts is unknown
    • Reconciliation of Fn14 pro-death (pyroptosis) vs. pro-proliferative (HPC) hepatic roles not provided
  16. 2024 High

    Defined a chromatin-level mechanism by which constitutive Fn14 signaling activates super-enhancers to drive NAMPT-dependent metabolic reprogramming and metastasis in TNBC.

    Evidence H3K27ac ChIP-seq, Hi-C chromatin looping, NAMPT inhibition, and in vivo xenograft metastasis with metabolic profiling

    PMID:38965263

    Open questions at the time
    • The transcription factors linking Fn14/NF-κB to super-enhancer activation not fully mapped
    • Whether this depends on TWEAK or on self-association not resolved
  17. 2025 High

    Revealed a protective, anti-fibrotic role for Fn14 in the lung, contrasting its profibrotic role elsewhere and identifying a specific pro-regenerative macrophage subset it supports.

    Evidence Fn14 knockout in bleomycin lung fibrosis with macrophage flow cytometry, ECM quantification, and organoid co-culture

    PMID:39827460

    Open questions at the time
    • Why Fn14 restrains fibroblasts in lung but activates them in heart/liver is mechanistically unexplained
    • Signaling branch mediating chemokine-driven macrophage recruitment not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how a single small receptor selects among its many downstream branches (canonical vs. non-canonical NF-κB, MRTF-A, TRAF3IP2, JAK2/STAT3, RIPK1-apoptosis, pyroptosis) to produce opposing tissue outcomes ranging from fibrosis promotion to fibrosis restraint.
  • No unifying structural or stoichiometric model links receptor clustering state to specific downstream branch selection
  • Determinants of pro- vs. anti-fibrotic outcomes across tissues not identified
  • TRAF-level recruitment code not experimentally defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2
Partners
FGFR1TRAF3IP2TWEAK

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 TWEAK binds Fn14 (TNFRSF12A) with physiological affinity; Fn14 is the cognate receptor for TWEAK and is a type I transmembrane protein and the smallest known TNFR superfamily member. Fn14 signals via recruitment of TNFR-associated factors (TRAFs). Receptor-ligand binding assays, cDNA cloning, transfection studies Cytokine & growth factor reviews High 12787562
2003 TWEAK-induced osteoclast differentiation of RAW264.7 macrophages is not mediated by Fn14/TweakR (no Fn14 surface expression detected by flow cytometry; Fn14-neutralizing antibodies did not block the effect), suggesting a second TWEAK receptor (TweakR2) exists on these cells. In contrast, TWEAK binding to Fn14 in HT-29 cells activated NF-κB and JNK but only weakly activated MAPK, whereas TweakR2 activated NF-κB, MAPK and JNK. Flow cytometry, neutralizing antibodies, cell differentiation assays, signaling pathway analysis The Journal of biological chemistry Medium 12794080
2003 Recombinant murine TWEAK bound to murine Fn14-transfected cells and induced cell death. Anti-Fn14 monoclonal antibodies cross-reacting with murine Fn14 also induced cell death in Fn14-transfected cells. Peritoneal macrophages secreted soluble functional TWEAK that was cytotoxic to Fn14-expressing cells. cDNA transfection, monoclonal antibody generation, cytotoxicity assays, functional neutralization Biochemical and biophysical research communications Medium 12821115
2009 Fn14 expression in cardiomyocytes is induced by FGF1, norepinephrine, angiotensin II, and mechanical stretch via the RhoA/ROCK kinase pathway; C3 exoenzyme (RhoA inhibitor), Y27632 (ROCK inhibitor), and siRNA knockdown of RhoA/ROCK each abolished Fn14 upregulation. TWEAK stimulation of Fn14-expressing cardiomyocytes promoted nuclear translocation of NF-κB and induced NF-κB-dependent genes (RANTES, MCP-1); siRNA knockdown of Fn14 inhibited TWEAK-induced NF-κB activation. siRNA knockdown, pharmacological inhibitors (C3 exoenzyme, Y27632), NF-κB nuclear translocation assay, neonatal rat cardiomyocyte culture Basic research in cardiology Medium 19629561
2013 Fn14 activation induces collagen expression in cardiac fibroblasts via RhoA-dependent nuclear translocation of myocardin-related transcription factor-A (MRTF-A/MAL). Fn14 activation also caused fibroblast proliferation and myofibroblast differentiation. Fn14 knockout mice showed substantially reduced RV fibrosis and dysfunction after pulmonary artery banding. Fn14 expression in cardiac fibroblasts is regulated by endothelin-1. Fn14 knockout mice, cell culture activation assays, RhoA/MRTF-A pathway analysis, histology Basic research in cardiology High 23325387
2013 Fn14 can self-associate into dimers independently of TWEAK binding; an 18-amino acid region within the Fn14 cytoplasmic domain mediates self-association. Dimerization occurs via an intermolecular disulfide bond at cysteine residue 122. A TWEAK-binding-deficient Fn14 deletion mutant retains the ability to activate the NF-κB pathway, demonstrating TWEAK-independent Fn14 signaling. Both endogenous and overexpressed Fn14 were detected in dimeric form under non-reducing SDS-PAGE. Deletion mutagenesis, non-reducing SDS-PAGE, NF-κB reporter assay in transfected cells, site-directed mutagenesis of Cys122 PloS one High 23750247
2013 Anti-Fn14 monoclonal antibodies (PDL192, P4A8) selectively activate the alternative (non-canonical) NF-κB pathway but do not activate classical NF-κB, IL-8 production, or cell death. Oligomerization of anti-Fn14 antibodies (via protein G or FcγR binding) converts them into full agonists mimicking membrane TWEAK, activating both classical and alternative NF-κB pathways. Soluble TWEAK predominantly triggers the alternative NF-κB pathway, while membrane-bound TWEAK triggers all Fn14-associated pathways. This indicates the alternative NF-κB pathway responds to Fn14 dimerization alone. NF-κB reporter assays, IL-8 ELISA, cell death assays, antibody oligomerization with protein G, FcγR-mediated cross-linking The Journal of biological chemistry High 23532848
2014 FGF receptor-1 (FGFR-1) physically interacts with Fn14 in cardiomyocytes, as shown by co-immunoprecipitation and proximity ligation assay. This interaction is enhanced by their respective ligands FGF1 and TWEAK. FGF1-induced cardiomyocyte cell cycle reentry is blocked by Fn14 inhibition, and TWEAK-induced cell cycle activation is blocked by FGFR-1 signaling inhibition. Co-stimulation with FGF1 and TWEAK synergistically promotes cell cycle reentry via PI3K/Akt signaling. Co-immunoprecipitation, proximity ligation assay, cell cycle assays with pharmacological and genetic inhibition, PI3K/Akt pathway analysis FASEB journal High 24571920
2014 Large-magnitude (12%) cyclic stretch induces Ca2+ influx and reactive oxygen species generation in osteoblasts, activating ASK1-JNK pathways, which transiently upregulate Fn14 gene expression. Cells with elevated Fn14 become sensitive to TWEAK-induced apoptosis. Small-magnitude (1%) stretch activates ERK and osteogenic gene expression, which is suppressed by JNK activated at high stretch. Cyclic stretch application, calcium imaging, ROS assays, gene expression analysis, JNK/p38 pathway inhibition, primary osteoblast validation The Journal of biological chemistry Medium 24446436
2014 Fn14 depletion inhibits bone metastasis in prostate cancer experimental models; functional reconstitution of Fn14 with constitutively active IKKβ rescues this phenotype, placing Fn14 upstream of IKKβ-dependent NF-κB signaling in bone metastasis. Androgen receptor (AR) binding to the Fn14 enhancer decreases Fn14 expression, establishing AR as a transcriptional repressor of Fn14. Fn14 siRNA depletion, IKKβ reconstitution, chromatin immunoprecipitation (AR binding to Fn14 enhancer), in vivo bone metastasis models Cancer research Medium 24970477
2014 Fn14 knockout in mice with RNA toxicity (myotonic dystrophy model) results in reduced muscle pathology and improved function. Anti-TWEAK antibody treatment similarly improved muscle histopathology and function. Fn14 induction in skeletal muscle correlates with NF-κB pathway activation in this disease context. Fn14 knockout mice, anti-TWEAK antibody treatment, muscle histopathology, functional assays, NF-κB pathway analysis Human molecular genetics High 25504044
2015 Fn14 expression in tumor cells (rather than host cells) is required for cancer-induced cachexia; tumors in Fn14-deficient or TWEAK-deficient hosts still cause cachexia comparable to wild-type mice, while anti-Fn14 antibodies targeting tumor Fn14 prevented tumor-induced inflammation and loss of fat and muscle mass, extending lifespan. Fn14-knockout and TWEAK-knockout mouse hosts with tumor transplantation, anti-Fn14 antibody treatment, body composition analysis Cell High 26359988
2017 TWEAK/Fn14 activation in hepatic stellate cells (LX-2 cells) promotes pro-inflammatory cytokine secretion (IL-8, IL-6, RANTES, MCP-1) via activation of NF-κB and STAT3 pathways. NF-κB and STAT3 interact with each other in this context, synergistically amplifying cytokine secretion. Fn14 siRNA knockdown inhibited these effects. ELISA, RT-PCR, Western blotting of pathway components, siRNA knockdown, co-immunoprecipitation of NF-κB/STAT3 interaction Molecular immunology Medium 28411440
2018 TRAF3IP2 (TRAF3 Interacting Protein 2) mediates TWEAK/Fn14-induced pro-fibrotic responses in cardiac fibroblasts. TWEAK upregulates TRAF3IP2 expression and promotes its nuclear translocation. Silencing TRAF3IP2 inhibited TWEAK-induced p38 MAPK, NF-κB and AP-1 activation, inflammatory cytokine expression, MMP/TIMP1 activation, collagen secretion, and fibroblast proliferation/migration. TRAF3IP2 knockout mice were protected from TWEAK-induced cardiac fibrosis and dysfunction in vivo. siRNA knockdown, TRAF3IP2 knockout mice, TWEAK infusion model, Western blotting, cardiac function assessment Journal of molecular and cellular cardiology High 29981796
2018 Visual experience induces Fn14 expression in excitatory thalamocortical neurons of the dorsal lateral geniculate nucleus. Fn14 knockout mice show deficits specifically in experience-dependent (not spontaneous activity-dependent) retinogeniculate refinement, with functionally weaker and structurally smaller retinogeniculate inputs, establishing Fn14 as a molecular link between sensory-driven gene expression and synaptic refinement. Single-nucleus RNA sequencing, Fn14 knockout mice, electrophysiology, structural synapse analysis Neuron High 30033152
2018 TWEAK/Fn14 activation in atrial myocytes mediates hypertrophy partly through the JAK2/STAT3 signaling pathway; siRNA inhibition of JAK2 or STAT3 attenuated TWEAK-induced HL-1 atrial myocyte hypertrophy. Fn14 knockdown counteracted TWEAK-induced increases in ANP and Troponin T. siRNA knockdown of Fn14, JAK2, and STAT3; measurement of hypertrophy markers (ANP, Troponin T, cell size) Journal of cellular and molecular medicine Medium 29971943
2018 TWEAK/Fn14 activation in keratinocytes promotes BP180 loss and reduced cell adhesion via activation of ERK and NF-κB pathways and downstream ADAM17. siRNA silencing of ADAM17 blocked TWEAK-induced BP180 loss, placing ADAM17 downstream of Fn14 signaling in this context. Fn14 siRNA preserved BP180 expression and protected cells from losing adherence. siRNA knockdown of Fn14 and ADAM17, Western blotting of ERK and NF-κB, cell adhesion assays The Journal of investigative dermatology Medium 28351660
2019 Fn14 expression is increased in dorsal root ganglion (DRG) neurons following peripheral nerve injury. Blocking Fn14 increase attenuated SNL-induced pain hypersensitivity. Conversely, mimicking Fn14 increase produced pain hypersensitivity in the absence of injury. Mechanistically, increased Fn14 activated the NF-κB pathway through promoting p65 nuclear translocation in injured DRG neurons. Spinal nerve ligation model, Fn14 siRNA knockdown, Fn14 overexpression, NF-κB p65 nuclear translocation assay, behavioral pain testing Molecular neurobiology Medium 30976982
2021 ThPOK (ZBTB7B) functions as a transcriptional repressor of TNFRSF12A (Fn14) by binding directly to the TNFRSF12A promoter. ThPOK knockdown elevated TNFRSF12A levels in gastric cancer cells. TNFRSF12A activates the NF-κB pathway and regulates T cell proliferation in a gastric cancer co-culture context. ChIP (ThPOK binding to TNFRSF12A promoter), siRNA knockdown, luciferase reporter, NF-κB pathway analysis, T cell co-culture assays Cytokine Medium 34353698
2023 Bile acids induce TNFRSF12A expression by enhancing c-JUN transcription factor binding to the TNFRSF12A promoter. TNFRSF12A then initiates hepatocyte pyroptosis via NFκB/Caspase-1/GSDMD signaling. Genetic ablation of Tnfrsf12a in cholestatic mice significantly reduced hepatocyte pyroptosis and cholestatic liver injury. TWEAK from infiltrated macrophages enhanced TNFRSF12A-induced hepatocyte pyroptosis. Tnfrsf12a knockout mice (BDL and DDC models), ChIP assay (c-JUN binding), Western blotting (Caspase-1, GSDMD cleavage), primary hepatocyte culture, human liver tissue samples Cell death discovery High 36690641
2022 TWEAK/Tnfrsf12a axis activates RIPK1-dependent apoptosis (not necroptosis or pyroptosis) in hepatocytes during acute liver failure. Inhibition of the TWEAK/Tnfrsf12a axis markedly attenuated acute liver failure in TAA and APAP models. This distinguishes Tnfrsf12a-induced cell death mechanism in hepatocytes as RIPK1-dependent apoptosis. Tnfrsf12a inhibition, TAA and APAP liver failure mouse models, RIPK1 pathway analysis, discrimination from necroptosis/pyroptosis by specific pathway inhibitors, human liver biopsy validation Cell death discovery Medium 35853848
2023 Fn14 is expressed by Prominin-1 (Prom1)-expressing hepatic progenitor cells (HPCs). TWEAK/Fn14 signaling promotes HPC proliferation and profibrogenic ductular reactions; Fn14 antagonism decreased ductular reactions, biliary fibrosis, periportal fibroblast activation, and noncanonical NF-κB signaling in a mouse model of biliary atresia. Recombinant TWEAK accelerated organoid growth, blocked by Fn14 antagonist. Fn14 antagonist treatment in RRV biliary atresia model, HPC organoid assays, CRISPR-based analysis, NF-κB signaling pathway analysis, RNA sequencing Hepatology (Baltimore, Md.) Medium 36626628
2023 Fn14 promotes myoblast fusion during skeletal muscle regeneration. Conditional deletion of Fn14 in myoblasts (but not differentiated myofibers) impairs muscle regeneration. Fn14 overexpression in myoblasts increases myotube diameter. Fn14 deletion reduces canonical Wnt and calcium signaling components; forced Wnt activation rescues fusion defects in Fn14-deficient myoblasts, placing Fn14 upstream of Wnt signaling in myoblast fusion. Conditional Fn14 knockout in myoblasts, global Fn14 knockout mice, Fn14 overexpression, muscle injury/regeneration model, Wnt pathway rescue experiments, in vitro differentiation assays Life science alliance High 37813488
2024 Constitutive Fn14 signaling in TNBC rewires the transcriptomic and epigenomic landscape, activating TNBC-specific super-enhancers (SEs) via chromatin looping to drive transcription of cancer dependency genes. One SE-driven target is NAMPT, whose upregulation promotes NAD+/ATP metabolic reprogramming critical for filopodia formation and metastasis. Fn14 overexpression/knockdown, H3K27ac ChIP-seq (super-enhancer mapping), Hi-C chromatin looping, NAMPT inhibition, in vivo xenograft metastasis models, metabolic profiling Nature communications High 38965263
2025 TWEAK-Fn14 signaling in lung fibroblasts/myofibroblasts inhibits fibroblast activation and ECM synthesis, and induces chemokine expression to recruit monocytes/macrophages. Fn14 deficiency increases ECM production, impairs macrophage infiltration/differentiation, and exacerbates bleomycin-induced lung fibrosis. Fn14 deficiency specifically diminishes an injury-induced SiglecF- CD11b- MHCIIlo intermediate macrophage subpopulation that promotes AT2 cell proliferation in organoids, indicating a protective role for Fn14 signaling in pulmonary fibrosis. Fn14 knockout mice, bleomycin lung fibrosis model, macrophage flow cytometry, organoid co-culture, ECM quantification Cell reports High 39827460
2011 Soluble TWEAK induced surface expression of RANKL by human immature STRO-1+ osteoblasts, establishing a mechanism by which TWEAK/Fn14 signaling could promote bone erosion indirectly through osteoblast-mediated osteoclastogenesis. Direct stimulation of PBMC by sTWEAK did not stimulate osteoclast formation. Flow cytometry for RANKL surface expression on osteoblasts, osteoclastogenesis assays from PBMC Arthritis research & therapy Medium 21435232
2013 TWEAK increased HMGB1 mRNA expression and protein secretion in monocytes via Fn14/NF-κB and PI3K signaling; blocking anti-Fn14 antibody or NF-κB/PI3K inhibitors reversed this effect. TWEAK-mediated HMGB1 increase was only observed in M1 macrophages, not M2 macrophages. TWEAK-induced MCP-1 secretion was blocked by HMGB1 siRNA, placing HMGB1 downstream of Fn14 in MCP-1 production. Anti-Fn14 blocking antibody, NF-κB and PI3K inhibitors, HMGB1 siRNA, ELISA, in vivo TWEAK injection and TWEAK-blocking antibodies in ApoE-/- mice Arteriosclerosis, thrombosis, and vascular biology Medium 23288170
2010 TWEAK acting on Fn14 induces apoptosis in endometrial cancer cells via caspase pathways, decreasing cell viability. Caspase activation assays, cell viability assays with recombinant TWEAK treatment Cancer letters Low 20189297
2014 TWEAK-Fn14 signaling induces NF-κB-dependent upregulation of Mcl-1 in NSCLC cells, conferring Mcl-1-dependent resistance to chemotherapy and radiotherapy. Depletion of Mcl-1 (siRNA or pharmacological inhibitor EU-5148) sensitized TWEAK-treated NSCLC cells to cisplatin and radiation. Inhibition of Bcl-2/Bcl-xL had minimal effect on TWEAK-induced survival. siRNA knockdown of Mcl-1 and Fn14, pharmacological Mcl-1 inhibitor, cisplatin/radiation survival assays, NF-κB pathway analysis Molecular cancer research Medium 24469836
2023 TWEAK-Fn14-RelB (alternative NF-κB) signaling axis promotes cancer stem-like cell features in ovarian cancer cells after chemotherapy, including spheroid formation, asymmetric division, SOX2 expression, and EMT gene expression (VIM, ZEB1). A small-molecule Fn14 inhibitor blocking this cascade prolongs survival following carboplatin in a mouse ovarian cancer model. Fn14 small-molecule inhibitor, spheroid formation assay, asymmetric division assay, gene expression analysis, in vivo mouse ovarian cancer model Molecular cancer research Medium 36214671
2012 NFAT1 transcription factor increases TWEAKR (Fn14) mRNA expression in breast cancer cells. The NFAT1-LCN2 axis regulates TWEAKR expression at the RNA level. TWEAKR mediates an anti-invasive effect in breast cancer cells. NFAT1 overexpression/knockdown, LCN2 expression analysis, TWEAKR expression measurement, invasion assays Journal of cell science Low 22767506
2014 HGF/MET receptor activation significantly upregulates Fn14 mRNA and protein expression in NSCLC cells. Fn14 depletion is sufficient to inhibit MET-driven NSCLC tumor cell migration and invasion in vitro, placing Fn14 downstream of MET signaling for invasion. HGF treatment, Fn14 siRNA knockdown, migration/invasion assays, protein expression analysis Clinical & experimental metastasis Medium 24710956

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 499 18404150
2003 TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that binds the TweakR/Fn14 receptor. Cytokine & growth factor reviews 254 12787562
2007 TWEAKing tissue remodeling by a multifunctional cytokine: role of TWEAK/Fn14 pathway in health and disease. Cytokine 246 17981048
2011 TWEAK/Fn14 pathway: an immunological switch for shaping tissue responses. Immunological reviews 182 22017434
2003 TWEAK mediates signal transduction and differentiation of RAW264.7 cells in the absence of Fn14/TweakR. Evidence for a second TWEAK receptor. The Journal of biological chemistry 132 12794080
2015 Targeting of Fn14 Prevents Cancer-Induced Cachexia and Prolongs Survival. Cell 128 26359988
2010 Regulation of tumor necrosis factor-like weak inducer of apoptosis receptor protein (TWEAKR) expression by Kaposi's sarcoma-associated herpesvirus microRNA prevents TWEAK-induced apoptosis and inflammatory cytokine expression. Journal of virology 115 20844036
2009 FGF-inducible 14-kDa protein (Fn14) is regulated via the RhoA/ROCK kinase pathway in cardiomyocytes and mediates nuclear factor-kappaB activation by TWEAK. Basic research in cardiology 97 19629561
2004 The role of TWEAK/Fn14 in the pathogenesis of inflammation and systemic autoimmunity. Frontiers in bioscience : a journal and virtual library 97 15353286
2013 Neuropsychiatric Lupus, the Blood Brain Barrier, and the TWEAK/Fn14 Pathway. Frontiers in immunology 80 24400009
2014 TWEAK/Fn14 axis: the current paradigm of tissue injury-inducible function in the midst of complexities. Seminars in immunology 79 24636536
2013 The TWEAK-Fn14 system as a potential drug target. British journal of pharmacology 78 23957828
2013 TWEAK/Fn14 pathway modulates properties of a human microvascular endothelial cell model of blood brain barrier. Journal of neuroinflammation 67 23320797
2013 Deletion of Fn14 receptor protects from right heart fibrosis and dysfunction. Basic research in cardiology 67 23325387
2015 The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics. Oncogene 63 26300004
2014 TWEAK/Fn14 Axis: A Promising Target for the Treatment of Cardiovascular Diseases. Frontiers in immunology 61 24478772
2014 TWEAK/Fn14 Signaling Axis Mediates Skeletal Muscle Atrophy and Metabolic Dysfunction. Frontiers in immunology 60 24478779
2021 The TWEAK/Fn14/CD163 axis-implications for metabolic disease. Reviews in endocrine & metabolic disorders 58 34542797
2020 TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression. Journal of hepatology 58 33221352
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
2017 TWEAK/Fn14 signaling in tumors. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 57 28639899
2012 The TWEAK/Fn14 pathway as an aggravating and perpetuating factor in inflammatory diseases: focus on inflammatory bowel diseases. Journal of leukocyte biology 57 22672874
2006 TWEAK and Fn14: new molecular targets for cancer therapy? Cancer letters 57 15885893
2018 Visual Experience-Dependent Expression of Fn14 Is Required for Retinogeniculate Refinement. Neuron 56 30033152
2017 TWEAK/Fn14 Activation Participates in Skin Inflammation. Mediators of inflammation 54 29038621
2018 miR-149-5p inhibits cell growth by regulating TWEAK/Fn14/PI3K/AKT pathway and predicts favorable survival in human osteosarcoma. International journal of immunopathology and pharmacology 52 30014744
2013 TWEAK/Fn14 and Non-Canonical NF-kappaB Signaling in Kidney Disease. Frontiers in immunology 51 24339827
2008 Induction of the cytokine TWEAK and its receptor Fn14 in ischemic stroke. Journal of the neurological sciences 51 18793781
2008 Expression of TWEAK and its receptor Fn14 in the multiple sclerosis brain: implications for inflammatory tissue injury. Journal of neuropathology and experimental neurology 51 19018248
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
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
2012 The TWEAK receptor Fn14 is a therapeutic target in melanoma: immunotoxins targeting Fn14 receptor for malignant melanoma treatment. The Journal of investigative dermatology 47 23190886
2009 Fn14-Fc fusion protein regulates atherosclerosis in ApoE-/- mice and inhibits macrophage lipid uptake in vitro. Arteriosclerosis, thrombosis, and vascular biology 47 19762780
2020 TWEAK/Fn14 axis is an important player in fibrosis. Journal of cellular physiology 45 33000480
2007 TWEAK and Fn14. New players in the pathogenesis of atherosclerosis. Frontiers in bioscience : a journal and virtual library 45 17485328
2006 Expression of TWEAK and its receptor Fn14 in human subcutaneous adipose tissue. Relationship with other inflammatory cytokines in obesity. Cytokine 45 16503147
2013 Fn14 in podocytes and proteinuric kidney disease. Biochimica et biophysica acta 44 23999007
2017 TWEAK/Fn14 Activation Contributes to the Pathogenesis of Bullous Pemphigoid. The Journal of investigative dermatology 43 28351660
2017 TWEAK/Fn14 promotes pro-inflammatory cytokine secretion in hepatic stellate cells via NF-κB/STAT3 pathways. Molecular immunology 41 28411440
2015 TWEAK/Fn14 activation induces keratinocyte proliferation under psoriatic inflammation. Experimental dermatology 41 26264384
2010 TWEAK/Fn14 promotes apoptosis of human endometrial cancer cells via caspase pathway. Cancer letters 41 20189297
2013 TWEAK-independent Fn14 self-association and NF-κB activation is mediated by the C-terminal region of the Fn14 cytoplasmic domain. PloS one 40 23750247
2011 TWEAK and Fn14 expression in the pathogenesis of joint inflammation and bone erosion in rheumatoid arthritis. Arthritis research & therapy 40 21435232
2013 Fibroblast growth factor inducible (Fn14)-specific antibodies concomitantly display signaling pathway-specific agonistic and antagonistic activity. The Journal of biological chemistry 38 23532848
2018 TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cultured cardiac fibroblasts and the heart. Journal of molecular and cellular cardiology 36 29981796
2014 Mcl-1 mediates TWEAK/Fn14-induced non-small cell lung cancer survival and therapeutic response. Molecular cancer research : MCR 36 24469836
2018 TWEAK/Fn14 Signals Mediate Burn Wound Repair. The Journal of investigative dermatology 35 30081003
2016 Role of the TWEAK/Fn14 pathway in autoimmune diseases. Immunologic research 35 26659091
2014 The expression of Fn14 via mechanical stress-activated JNK contributes to apoptosis induction in osteoblasts. The Journal of biological chemistry 35 24446436
2014 TWEAK-Fn14 Cytokine-Receptor Axis: A New Player of Myocardial Remodeling and Cardiac Failure. Frontiers in immunology 35 24611063
2013 HMGB1 expression and secretion are increased via TWEAK-Fn14 interaction in atherosclerotic plaques and cultured monocytes. Arteriosclerosis, thrombosis, and vascular biology 35 23288170
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 34 29681850
2023 Hepatic TNFRSF12A promotes bile acid-induced hepatocyte pyroptosis through NFκB/Caspase-1/GSDMD signaling in cholestasis. Cell death discovery 33 36690641
2014 TWEAK/Fn14, a pathway and novel therapeutic target in myotonic dystrophy. Human molecular genetics 33 25504044
2020 TWEAK/Fn14 axis in respiratory diseases. Clinica chimica acta; international journal of clinical chemistry 31 32526219
2017 Regulation of Neuroinflammation: What Role for the Tumor Necrosis Factor-Like Weak Inducer of Apoptosis/Fn14 Pathway? Frontiers in immunology 31 29201025
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 30 34646379
2018 Fn14 deficiency ameliorates psoriasis-like skin disease in a murine model. Cell death & disease 30 30038329
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
2015 Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD. Blood 29 26012567
2012 Expression of TweakR in breast cancer and preclinical activity of enavatuzumab, a humanized anti-TweakR mAb. Journal of cancer research and clinical oncology 29 23073510
2013 TWEAK/Fn14 signaling mediates gastric cancer cell resistance to 5-fluorouracil via NF-κB activation. International journal of oncology 28 24337061
2020 Controversies in TWEAK-Fn14 signaling in skeletal muscle atrophy and regeneration. Cellular and molecular life sciences : CMLS 27 32200423
2014 TWEAK/Fn14 pathway is a novel mediator of retinal neovascularization. Investigative ophthalmology & visual science 27 24408972
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 27 24571920
2021 Fn14-targeted BiTE and CAR-T cells demonstrate potent preclinical activity against glioblastoma. Oncoimmunology 26 34595061
2018 TWEAK/Fn14 mediates atrial-derived HL-1 myocytes hypertrophy via JAK2/STAT3 signalling pathway. Journal of cellular and molecular medicine 26 29971943
2013 Functional expression of TWEAK and the receptor Fn14 in human malignant ovarian tumors: possible implication for ovarian tumor intervention. PloS one 26 23469193
2013 TWEAK and Fn14 in the Neurovascular Unit. Frontiers in immunology 26 24273541
2021 TWEAK-Fn14 as a common pathway in the heart and the kidneys in cardiorenal syndrome. The Journal of pathology 25 33512736
2017 Knockdown of the differentially expressed gene TNFRSF12A inhibits hepatocellular carcinoma cell proliferation and migration in vitro. Molecular medicine reports 25 28138696
2023 TWEAK/FN14 promotes profibrogenic pathway activation in Prominin-1-expressing hepatic progenitor cells in biliary atresia. Hepatology (Baltimore, Md.) 24 36626628
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
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
2013 Expression of TWEAK/Fn14 in neuroblastoma: implications in tumorigenesis. International journal of oncology 22 23443741
2024 TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in triple-negative breast cancer. Nature communications 21 38965263
2017 TWEAK/Fn14 promotes oxidative stress through AMPK/PGC‑1α/MnSOD signaling pathway in endothelial cells. Molecular medicine reports 21 29257217
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
2012 The role of TWEAK/Fn14 in cardiac remodeling. Molecular biology reports 20 22752727
2012 Lipocalin 2, the TNF-like receptor TWEAKR and its ligand TWEAK act downstream of NFAT1 to regulate breast cancer cell invasion. Journal of cell science 20 22767506
2024 Integrative single-cell and spatial transcriptomic analyses identify a pathogenic cholangiocyte niche and TNFRSF12A as therapeutic target for biliary atresia. Hepatology (Baltimore, Md.) 19 39178365
2023 TWEAK-Fn14-RelB Signaling Cascade Promotes Stem Cell-like Features that Contribute to Post-Chemotherapy Ovarian Cancer Relapse. Molecular cancer research : MCR 19 36214671
2022 Inhibition of TWEAK/Tnfrsf12a axis protects against acute liver failure by suppressing RIPK1-dependent apoptosis. Cell death discovery 19 35853848
2021 ThPOK transcriptionally inactivates TNFRSF12A to increase the proliferation of T cells with the involvement of the NF-kB pathway. Cytokine 19 34353698
2025 TWEAK-Fn14 signaling protects mice from pulmonary fibrosis by inhibiting fibroblast activation and recruiting pro-regenerative macrophages. Cell reports 18 39827460
2022 Targeting fibroblast growth factor (FGF)-inducible 14 (Fn14) for tumor therapy. Frontiers in pharmacology 18 36339601
2017 Lipopolysaccharide Upregulated Intestinal Epithelial Cell Expression of Fn14 and Activation of Fn14 Signaling Amplify Intestinal TLR4-Mediated Inflammation. Frontiers in cellular and infection microbiology 18 28744451
2023 Fn14 promotes myoblast fusion during regenerative myogenesis. Life science alliance 17 37813488
2014 FN14 expression correlates with MET in NSCLC and promotes MET-driven cell invasion. Clinical & experimental metastasis 17 24710956
2013 Fn14•TRAIL effectively inhibits hepatocellular carcinoma growth. PloS one 17 24130833
2017 Fn14·TRAIL fusion protein is oligomerized by TWEAK into a superefficient TRAIL analog. Cancer letters 16 28455246

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