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Showing TNFSF12 — TWEAK is a alias.

TNFSF12

Tumor necrosis factor ligand superfamily member 12 · UniProt O43508

Length
249 aa
Mass
27.2 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFSF12 (TWEAK) is a type II transmembrane cytokine of the TNF superfamily that is shed as a biologically active soluble ligand and signals through the small TNF-receptor-family member Fn14/TweakR (TNFRSF12A), to which it binds with nanomolar affinity and whose cytoplasmic tail recruits TRAFs 1, 2, and 3 (PMID:11728344, PMID:12787562). Engagement of Fn14 drives context-dependent outcomes spanning proliferation, cell death, inflammation, and metabolic/epigenetic reprogramming. TWEAK is mitogenic for tissue progenitor cells, expanding liver oval/progenitor cells in an Fn14-dependent manner (PMID:16110324) and promoting hepatic progenitor ductular reactions and myoblast fusion through low-dose activation of the non-canonical NF-κB pathway (NIK/IKKα/p100/RelB) (PMID:23074266, PMID:36626628). In parallel, TWEAK triggers cell-type-specific death programs—caspase-8/3-dependent apoptosis, cathepsin B-dependent necrosis upon caspase inhibition (PMID:11777967), and an Fn14/RIPK3/MLKL-dependent late wave of necroptosis in injured renal tubules (PMID:29588419)—while an early study showed that in some lines TWEAK-induced apoptosis is relayed indirectly through endogenous TNF/TNFR1 signaling (PMID:10382740). As a pro-inflammatory effector, TWEAK activates canonical NF-κB, MAPK (ERK/JNK/p38) and AP-1, JAK2/STAT3, and PI3K pathways to induce chemokines, cytokines, HMGB1, endothelin-1/ECE-1, and VEGF, and transactivates EGFR via ADAM17-mediated shedding of HB-EGF/TGFα (PMID:24037740, PMID:23288170, PMID:28411440, PMID:28025386, PMID:19398263), with TRAF3IP2 acting as a causal amplifying intermediate in cardiac fibroblasts (PMID:29981796). TWEAK also reprograms cellular state by directing RelA-dependent histone deacetylation at the Klotho and PGC-1α promoters to repress these genes and impair mitochondrial function (PMID:21719790, PMID:26535995), and in triple-negative breast cancer drives super-enhancer activation of NAMPT to enable NAD+/ATP metabolic reprogramming and metastasis (PMID:38965263). Soluble TWEAK can be scavenged by the macrophage receptor CD163, which competes with Fn14 for ligand binding and limits TWEAK-driven tumor cell apoptosis (PMID:17548657). Pathologically, TWEAK/Fn14 contributes to psoriatic skin inflammation through synergy with TNF and IL-17A (PMID:34797693) and promotes colorectal cancer EMT and liver metastasis when secreted by Th17 cells (PMID:38335276).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 Medium

    Established that TWEAK-induced death in some cells is not cell-intrinsic but relayed through endogenous TNF/TNFR1, and that TWEAK acts via a receptor other than the death-domain receptor DR3.

    Evidence Neutralizing antibody and TNFR1-Fc blockade plus RT-PCR for receptor expression in Kym-1 cells

    PMID:10382740

    Open questions at the time
    • The non-death-domain TWEAK receptor was undefined at this stage
    • Did not identify Fn14 as the direct receptor
  2. 2001 High

    Identified Fn14/TweakR as the high-affinity TWEAK receptor and defined its proximal signaling machinery, resolving the previously undefined receptor and linking TWEAK to angiogenesis and endothelial growth.

    Evidence Receptor cloning, five orthogonal binding assays (Kd ~2.3 nM), TRAF1/2/3 pulldowns, HUVEC proliferation/migration and in vivo corneal angiogenesis

    PMID:11728344

    Open questions at the time
    • Downstream transcriptional outputs not mapped
    • TRAF-to-NF-κB coupling not yet dissected
  3. 2002 High

    Showed that TWEAK engages multiple distinct death pathways in a cell-type-specific manner, establishing mechanistic bifurcation between caspase-dependent apoptosis and cathepsin B-dependent necrosis.

    Evidence Caspase activity assays, pharmacological caspase/cathepsin inhibitors, and cathepsin B subcellular fractionation across HSC3 and HT-29 lines

    PMID:11777967

    Open questions at the time
    • Receptor identity confirmed only as non-DR3, not directly Fn14
    • Molecular switch controlling apoptosis-vs-necrosis not defined
  4. 2003 Medium

    Confirmed TWEAK as a type II transmembrane protein shed as an active soluble cytotoxic cytokine acting on Fn14-expressing targets.

    Evidence cDNA transfection, macrophage secretion, cytotoxicity and mAb neutralization assays; review synthesis of cloning/binding data

    PMID:12787562 PMID:12821115

    Open questions at the time
    • Sheddase responsible for soluble TWEAK generation not identified
    • Quantitative contribution of membrane vs soluble form unresolved
  5. 2005 High

    Demonstrated genetically that TWEAK is a selective progenitor-cell mitogen acting through Fn14, establishing a regenerative/proliferative role distinct from its death-inducing activity.

    Evidence Fn14-null and transgenic mice, adenoviral TWEAK, anti-TWEAK mAb, and oval cell proliferation assays

    PMID:16110324

    Open questions at the time
    • Intracellular signaling driving oval cell proliferation not defined here
    • Selectivity for progenitors over mature hepatocytes mechanistically unexplained
  6. 2007 Medium

    Identified CD163 as an alternate scavenger receptor that competes with Fn14 for TWEAK, introducing a ligand-sequestration mechanism that tunes TWEAK availability.

    Evidence Competition binding assays, CHO transfection binding, and monocyte sequestration reversing tumor cell apoptosis

    PMID:17548657

    Open questions at the time
    • Physiological significance of CD163 scavenging in vivo not established
    • Whether CD163 transduces signal or only sequesters unresolved
  7. 2011 High

    Revealed an epigenetic repressive arm of TWEAK signaling, where RelA directs histone deacetylation at the Klotho promoter to downregulate the gene.

    Evidence ChIP for RelA occupancy and histone deacetylation, NF-κB/HDAC inhibitors, and in vivo TWEAK/anti-TWEAK in tubular cells

    PMID:21719790

    Open questions at the time
    • Specific HDAC recruited not identified
    • Generality beyond renal tubular cells not tested
  8. 2012 High

    Defined the non-canonical NF-κB (NIK/IKKα/p100/RelB) pathway as the low-dose TWEAK output controlling myoblast fusion, separating it from canonical NF-κB signaling.

    Evidence Genetic knockdown of p100/RelB/IKKα/NIK, cIAP1 knockout, and multinucleation assays

    PMID:23074266

    Open questions at the time
    • Dose threshold mechanism switching canonical vs non-canonical not molecularly defined
    • Fusion machinery targets downstream of RelB unidentified
  9. 2013 High

    Dissected TWEAK-driven inflammation into EGFR-dependent and -independent arms, identifying ADAM17-mediated EGFR ligand shedding as a transactivation route to ERK and proinflammatory genes.

    Evidence Erlotinib and ADAM17 inhibitor treatment in vivo and in vitro with phospho-EGFR/ERK readouts; HMGB1/PI3K-NF-κB dissection in M1 macrophages

    PMID:23288170 PMID:24037740

    Open questions at the time
    • Mechanism of Fn14-to-ADAM17 coupling not defined
    • HMGB1 study (#11) is Medium-confidence single-lab
  10. 2016 High

    Extended the epigenetic repression model to PGC-1α, linking TWEAK/NF-κB-directed histone deacetylation to mitochondrial dysfunction, and revealed AP-1/NF-κB-driven endothelin induction.

    Evidence ChIP for H3 deacetylation at PGC-1α promoter, PGC-1α rescue, mitochondrial membrane potential; ECE-1 promoter mapping and EMSA for the endothelin axis

    PMID:26535995 PMID:28025386

    Open questions at the time
    • Endothelin/SIRT1 findings vary in confidence and tissue
    • Connection between mitochondrial repression and cell fate not established
  11. 2018 High

    Established TWEAK/Fn14 as a driver of RIPK1/RIPK3/MLKL-dependent necroptosis and of TRAF3IP2-amplified pro-fibrotic and JAK2/STAT3-hypertrophic responses, broadening the cell-fate and tissue-remodeling repertoire.

    Evidence RIPK3/MLKL/Fn14 knockouts and necrostatin-1 in AKI; TRAF3IP2 KO/siLNA in cardiac fibroblasts; JAK2/STAT3/Fn14 siRNA in atrial myocytes

    PMID:29588419 PMID:29971943 PMID:29981796

    Open questions at the time
    • What dictates necroptosis vs apoptosis timing in tissue not fully resolved
    • TRAF3IP2 positive-feedback initiation trigger unknown
  12. 2021 High

    Demonstrated cell-type-specific, genetically defined roles for Fn14 in epithelial pathology—keratinocyte-driven psoriatic inflammation via TWEAK/TNF/IL-17A synergy and hepatic progenitor non-canonical NF-κB-driven biliary fibrosis.

    Evidence Keratinocyte-specific Fn14 KO in imiquimod model with keratinocyte transcriptomics; Fn14 antagonist and HPC organoid rescue in biliary atresia model

    PMID:34797693 PMID:36626628

    Open questions at the time
    • Molecular basis of TWEAK/TNF/IL-17 transcriptional synergy not fully mapped
    • Progenitor-specific signaling components incompletely defined
  13. 2024 High

    Uncovered an oncogenic epigenomic-metabolic axis in which Fn14 activates super-enhancers to upregulate NAMPT-driven NAD+/ATP metabolism enabling metastasis, and showed Th17-derived TWEAK drives EMT and colorectal liver metastasis.

    Evidence H3K27ac ChIP-seq, chromatin looping, NAMPT inhibition and metabolomics in TNBC; CRISPR/siRNA Fn14 KO and Tnfsf12-KO mice in CRC metastasis models

    PMID:38335276 PMID:38965263

    Open questions at the time
    • How Fn14 signaling reaches super-enhancer machinery not mechanistically resolved
    • Therapeutic targetability of the TWEAK-NAMPT axis untested clinically

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single TWEAK/Fn14 axis selects among proliferation, apoptosis, necroptosis, inflammation, and epigenetic/metabolic reprogramming—and what molecular thresholds (ligand dose, cIAP/TRAF state, co-stimulatory context) govern the switch—remains unresolved.
  • No unifying model linking receptor occupancy to fate choice
  • Sheddase generating soluble TWEAK and its regulation undefined
  • In vivo balance between Fn14 signaling and CD163 scavenging unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-4839726 Chromatin organization 3 R-HSA-1643685 Disease 2 R-HSA-5357801 Programmed Cell Death 2
Partners
CD163TNFRSF12ATRAF1TRAF2TRAF3TRAF3IP2

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 TWEAK binds a novel TNF receptor superfamily member (TweakR/Fn14) cloned from a human umbilical vein endothelial cell library; the interaction has an affinity constant (Kd) of 2.3 ± 0.1 nM as measured by five independent binding assays. The TweakR cytoplasmic domain binds TRAFs 1, 2, and 3. Cross-linking of TweakR induces HUVEC growth, and soluble TweakR inhibits endothelial cell migration in vitro and corneal angiogenesis in vivo. Receptor cloning, five binding assays, TRAF pulldown/binding assays, HUVEC proliferation and migration assays, in vivo corneal angiogenesis model Immunity High 11728344
1999 TWEAK-induced apoptosis in Kym-1 cells is indirect, mediated by endogenous TNF signaling through TNFR1; TNFR1-Fc fusion protein, neutralizing anti-TNF antibodies, and TNFR1-specific Fab fragments each blocked cell death. TWEAK also co-stimulates TNFR1-mediated cell death. Kym-1 cells do not express DR3/APO3 at protein or mRNA level, indicating a separate, undefined non-death-domain TWEAK receptor. Neutralizing antibody blockade, TNFR1-Fc fusion protein, flow cytometry binding assay, RT-PCR for receptor expression European journal of immunology Medium 10382740
2002 TWEAK induces multiple cell-death pathways in a cell-type-specific manner: (1) caspase-8 and caspase-3 dependent apoptosis in HSC3 cells; (2) cathepsin B-dependent necrosis in IFN-γ-treated HT-29 cells, accompanied by cytosolic release of cathepsin B from lysosomes. Pan-caspase inhibition switches HT-29 death to necrosis. None of the TWEAK-sensitive lines express DR3, confirming TWEAK acts through a receptor distinct from DR3. Caspase activity assays, caspase and lysosomal proteinase inhibitors, cathepsin B subcellular fractionation, flow cytometry receptor binding, RT-PCR and western for DR3 Journal of immunology High 11777967
2005 TWEAK selectively stimulates proliferation of liver oval (progenitor) cells but has no mitogenic effect on mature hepatocytes. This mitogenic activity is mediated through the Fn14 receptor: TWEAK-expressing adenovirus induces oval cell expansion in wild-type but not Fn14-null mice, and a blocking anti-TWEAK mAb reduces DDC-induced oval cell expansion. Transgenic mouse overexpression, Fn14-null mouse genetic model, adenoviral TWEAK delivery, anti-TWEAK blocking mAb, oval cell culture proliferation assay The Journal of clinical investigation High 16110324
2007 CD163, a scavenger receptor on monocytes/macrophages, binds TWEAK with dose-dependent affinity. In competition assays, soluble CD163 and Fn14 competitively displace TWEAK from their respective coated binding partners. Monocytes (Fn14-negative, CD163-positive) can sequester TWEAK from supernatants, preventing tumor cell apoptosis; this was reversed by an anti-CD163 mAb or a CD163-mimicking peptide. Recombinant TWEAK binding to CD163-transfected CHO cells was inhibited by unlabeled TWEAK or Hp-Hb complex. Combinatorial peptide library screen, dose-dependent binding assay, competition binding assay, flow cytometry, immunofluorescence, CHO cell transfection binding assay, functional apoptosis assay Journal of immunology Medium 17548657
2011 TWEAK and TNFα reduce renal Klotho expression through an NF-κB-dependent mechanism: TWEAK activates NF-κB and promotes RelA binding to the Klotho promoter with accompanying histone deacetylation, as shown by chromatin immunoprecipitation. NF-κB inhibition with parthenolide and HDAC inhibitor treatment each reversed TWEAK-induced Klotho downregulation. Chromatin immunoprecipitation (ChIP), siRNA knockdown of IκBα, NF-κB and HDAC inhibitor pharmacology, in vivo TWEAK administration with TWEAK blockade/KO, tubular cell culture Journal of the American Society of Nephrology High 21719790
2012 TWEAK at low concentrations preferentially activates the non-canonical NF-κB pathway and increases myoblast fusion. Loss of cIAP1 constitutively activates non-canonical NF-κB and amplifies fusion; knockdown of p100, RelB, IKKα, or NIK attenuates fusion in wild-type myoblasts, placing non-canonical NF-κB signaling downstream of TWEAK-Fn14 in the regulation of myoblast fusion. Genetic knockdown (siRNA), cIAP1 knockout cells, p52/RelB overexpression, TRAF3 depletion, NF-κB pathway component manipulation, multinucleation counting assay Science signaling High 23074266
2013 TWEAK transactivates the EGFR in renal tubular cells via Fn14 binding, leading to ADAM17 activation and release of EGFR ligands HB-EGF and TGFα. EGFR transactivation drives ERK activation and proinflammatory gene upregulation, while NF-κB activation is EGFR-independent. In vivo, erlotinib (EGFR kinase inhibitor) and WTACE-2 (ADAM17 inhibitor) blocked TWEAK-induced renal EGFR phosphorylation and inflammation. In vivo TWEAK administration with erlotinib or ADAM17 inhibitor treatment, in vitro kinase inhibitor assays, western blotting for phospho-EGFR/ERK, anti-EGFR/ADAM17/ERK inhibitors The Journal of pathology High 24037740
2016 TWEAK decreases PGC-1α expression and mitochondrial function in renal tubular cells through an NF-κB-dependent mechanism involving histone H3 deacetylation at the PGC-1α promoter. Adenoviral PGC-1α overexpression prevents TWEAK-induced mitochondrial membrane potential loss. NF-κB or HDAC inhibitors prevented TWEAK-induced PGC-1α downregulation. Chromatin immunoprecipitation (H3 deacetylation at PGC-1α promoter), adenoviral PGC-1α overexpression rescue, NF-κB and HDAC pharmacological inhibitors, in vivo anti-TWEAK antibody treatment, mitochondrial membrane potential measurement Kidney international High 26535995
2018 TWEAK/Fn14 activation drives a second wave of necroptosis in acute kidney injury (AKI) at 72–96 h: TWEAK induces apoptosis in a proinflammatory environment in tubular cells, but caspase inhibition switches death to necroptosis. Genetic deficiency of RIPK3, MLKL, or Fn14, or treatment with necrostatin-1 (RIPK1 inhibitor), prevented late-phase cell death and renal dysfunction but not early injury (48 h). Genetic knockouts (RIPK3-KO, Fn14-KO), MLKL deficiency, necrostatin-1 pharmacology, folic acid-induced AKI mouse model, in vitro tubular cell death assays with caspase inhibition Proceedings of the National Academy of Sciences High 29588419
2018 TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cardiac fibroblasts: forced TRAF3IP2 expression upregulates TWEAK and TWEAKR; exogenous TWEAK upregulates TRAF3IP2 in a dose/time-dependent manner (positive feedback). TRAF3IP2 silencing inhibits TWEAK-induced p38 MAPK, NF-κB and AP-1 activation, inflammatory cytokine expression, MMP/TIMP1, collagen secretion, and fibroblast proliferation/migration. TWEAK infusion in vivo induces cardiac TRAF3IP2, NF-κB/AP-1, fibrosis and dysfunction; genetic TRAF3IP2 ablation prevents these changes. siRNA silencing, forced expression, western blotting, in vivo TWEAK infusion with TRAF3IP2 knockout mice, collagen secretion assay, migration assay Journal of molecular and cellular cardiology High 29981796
2013 TWEAK increases HMGB1 mRNA expression and protein secretion in monocyte/macrophage (THP-1) cells via Fn14 binding and NF-κB and PI3K pathway activation; this effect is restricted to M1 macrophages and not M2. TWEAK-induced HMGB1 in turn promotes MCP-1 secretion (blocked by HMGB1 siRNA). In vivo, systemic TWEAK injection in ApoE-/- mice elevated aortic HMGB1; anti-TWEAK antibodies reduced it. Blocking anti-Fn14 antibody, NF-κB and PI3K pharmacological inhibitors, HMGB1 siRNA, in vivo TWEAK injection and anti-TWEAK antibody treatment in ApoE-/- mice, ELISA, qPCR Arteriosclerosis, thrombosis, and vascular biology Medium 23288170
2017 TWEAK promotes pro-inflammatory cytokine secretion (IL-8, IL-6, RANTES, MCP-1) in activated hepatic stellate cells (LX-2) via concurrent NF-κB and STAT3 pathway activation; STAT3 and NF-κB interact with each other, and siRNA knockdown of either pathway component reduces cytokine output synergistically. siRNA knockdown of NF-κB and JAK2/STAT3 components, western blotting for phosphorylated signaling proteins, ELISA for cytokines, RT-PCR Molecular immunology Medium 28411440
2016 TWEAK upregulates endothelin-converting enzyme-1 (ECE-1) and endothelin-1 (ET-1) in endothelial cells via AP-1 (ERK1/2 and JNK pathways) and NF-κB transcriptional activation, demonstrated by ECE-1 promoter serial deletion assays, EMSA for AP-1/NF-κB binding, and pharmacological inhibitors of ERK1/2 (PD-98059), JNK (SP-600125), and NF-κB (PDTC). In vivo TWEAK administration elevated ET-1 and ECE-1 in mouse aorta/lung and induced transient hypertension. ECE-1 promoter deletion/transfection assays, EMSA, ERK/JNK/NF-κB pharmacological inhibitors, in vivo TWEAK injection, ELISA, qPCR, western blotting Cardiovascular research Medium 28025386
2009 TWEAK promotes ovarian cancer cell migration, invasion, and VEGF upregulation via NF-κB pathway activation: TWEAK treatment causes NF-κB nuclear translocation, and NF-κB inhibition (PDTC) suppresses TWEAK-induced VEGF expression and metastatic behavior in HO-8910PM cells. NF-κB nuclear translocation assay, NF-κB pharmacological inhibition (PDTC), VEGF protein measurement, migration/invasion assays Cancer letters Medium 19398263
2018 TWEAK/Fn14 activation promotes atrial myocyte hypertrophy (HL-1 cells) via JAK2/STAT3 signaling: TWEAK increased ANP and Troponin T expression and cell size; siRNA knockdown of JAK2 or STAT3 attenuated TWEAK-induced hypertrophy; Fn14 knockdown counteracted TWEAK effects. siRNA knockdown of JAK2, STAT3, and Fn14; western blotting for ANP and Troponin T; cell size measurement Journal of cellular and molecular medicine Medium 29971943
2014 TWEAK induces RANKL surface expression on immature STRO-1+ human osteoblasts, providing a mechanism for TWEAK-mediated bone erosion in rheumatoid arthritis. Soluble TWEAK did not directly stimulate osteoclast formation from PBMCs (negative result for direct osteoclastogenesis). Flow cytometry for surface RANKL on osteoblasts, PBMC osteoclastogenesis assay with sTWEAK, immunohistochemistry for TWEAK/Fn14 in RA synovium Arthritis research & therapy Medium 21435232
2003 Murine TWEAK is expressed as a functional cell-surface protein on TWEAK-transfected cells and is secreted by thioglycolate-elicited peritoneal macrophages; the secreted form is cytotoxic against Fn14-expressing target cells and is neutralized by an anti-murine TWEAK mAb (MTW-1). cDNA transfection, anti-TWEAK and anti-Fn14 mAb generation, flow cytometry, cytotoxicity assay, neutralization assay Biochemical and biophysical research communications Medium 12821115
2003 TWEAK is identified as a type II transmembrane protein that can be shed as a biologically active soluble form. Its only known signaling receptor is Fn14/TweakR, the smallest TNFR superfamily member, which signals via TRAF recruitment. Literature synthesis of cloning studies and binding characterization Cytokine & growth factor reviews Medium 12787562
2021 In psoriasis, TWEAK strongly synergizes with TNF and IL-17A to upregulate psoriasis-associated genes (IL23A, IL36G, CXC chemokines) in human keratinocytes. Fn14 (TNFRSF12A), the TWEAK receptor, is expressed in keratinocytes; keratinocyte-specific deletion of Fn14 reduced imiquimod-induced skin inflammation and epidermal hyperplasia in mice. Keratinocyte-specific Fn14 knockout mice, imiquimod psoriasis model, transcriptomic analysis in human keratinocytes, recombinant cytokine stimulation Science immunology High 34797693
2024 TWEAK secreted by Th17 cells promotes epithelial-mesenchymal transition (EMT) and colorectal cancer liver metastasis by binding Fn14 on tumor cells, activating downstream migration and invasion. CRISPR knockout or siRNA-mediated knockdown of Fn14 in tumor cells reduced metastasis and prolonged survival in mouse models. CRISPR-Cas9 Fn14 knockout, siRNA knockdown with lipid nanoparticles, mouse metastasis models, single-cell RNA sequencing, Tnfsf12-knockout mice Cancer research High 38335276
2016 TWEAK increases SIRT1 expression and promotes p53 deacetylation in activated hepatic stellate cells (LX-2), suppressing cellular senescence (SA-β-Gal activity); Fn14 membrane expression was markedly upregulated by TWEAK, which enhanced cell viability. Western blotting for SIRT1 and ac-p53, RT-PCR, SA-β-Gal senescence assay, Fn14 expression quantification Cell biology international Low 27888541
2021 TWEAK/Fn14 signaling in Prominin-1-expressing hepatic progenitor cells activates non-canonical NF-κB signaling, driving profibrogenic ductular reactions in biliary atresia. Fn14 antagonism decreased ductular reactions, biliary fibrosis, and periportal fibroblast activation in a mouse model; recombinant TWEAK accelerated murine HPC organoid growth, an effect abolished by Fn14 antagonism. Fn14 antagonist (L524-0366) in vivo, murine HPC organoid proliferation assay with recombinant TWEAK and antagonist, immunohistochemistry, non-canonical NF-κB pathway western blotting Hepatology Medium 36626628
2017 TWEAK/Fn14 activation in bullous pemphigoid keratinocytes (HaCaT cells) reduces BP180 expression and cellular adherence via ERK and NF-κB pathway activation and downstream ADAM17 activity; ADAM17 siRNA knockdown preserved BP180 and protected cell adherence. Fn14 siRNA, ADAM17 siRNA, ERK and NF-κB pathway inhibition, BP180 expression by western blot, cell adherence assay The Journal of investigative dermatology Medium 28351660
2024 Constitutive Fn14 signaling in TNBC rewires the epigenomic landscape by activating TNBC-specific super-enhancers (via chromatin looping) to transcriptionally upregulate NAMPT, driving NAD+/ATP metabolic reprogramming critical for filopodia formation and metastasis. Fn14 constitutive expression/knockdown, super-enhancer mapping (H3K27ac ChIP-seq), chromatin looping assay, NAMPT inhibition, metabolomics (NAD+/ATP), filopodia formation assay, in vivo metastasis model Nature communications High 38965263

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
2011 The inflammatory cytokines TWEAK and TNFα reduce renal klotho expression through NFκB. Journal of the American Society of Nephrology : JASN 347 21719790
2005 TWEAK induces liver progenitor cell proliferation. The Journal of clinical investigation 336 16110324
2001 A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis. Immunity 330 11728344
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
2007 A previously unrecognized protein-protein interaction between TWEAK and CD163: potential biological implications. Journal of immunology (Baltimore, Md. : 1950) 197 17548657
2011 TWEAK/Fn14 pathway: an immunological switch for shaping tissue responses. Immunological reviews 182 22017434
2002 Multiple pathways of TWEAK-induced cell death. Journal of immunology (Baltimore, Md. : 1950) 149 11777967
1999 TWEAK can induce cell death via endogenous TNF and TNF receptor 1. European journal of immunology 140 10382740
2018 TWEAK and RIPK1 mediate a second wave of cell death during AKI. Proceedings of the National Academy of Sciences of the United States of America 132 29588419
2006 TWEAK is a novel arthritogenic mediator. Journal of immunology (Baltimore, Md. : 1950) 132 16888023
2004 TWEAK can induce pro-inflammatory cytokines and matrix metalloproteinase-9 in macrophages. Circulation journal : official journal of the Japanese Circulation Society 123 15056843
2016 The inflammatory cytokine TWEAK decreases PGC-1α expression and mitochondrial function in acute kidney injury. Kidney international 118 26535995
2011 TWEAK, a multifunctional cytokine in kidney injury. Kidney international 97 21697814
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 Role of TWEAK in lupus nephritis: a bench-to-bedside review. Journal of autoimmunity 95 22727560
2014 TWEAK and the progression of renal disease: clinical translation. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 92 24493870
2017 Endoplasmic reticulum chaperones tweak the mitochondrial calcium rheostat to control metabolism and cell death. Cell calcium 87 28619231
2017 Role of Omentin, Vaspin, Cardiotrophin-1, TWEAK and NOV/CCN3 in Obesity and Diabetes Development. International journal of molecular sciences 85 28809783
2012 TWEAK and TRAF6 regulate skeletal muscle atrophy. Current opinion in clinical nutrition and metabolic care 84 22366923
2013 Neuropsychiatric Lupus, the Blood Brain Barrier, and the TWEAK/Fn14 Pathway. Frontiers in immunology 80 24400009
2021 TWEAK functions with TNF and IL-17 on keratinocytes and is a potential target for psoriasis therapy. Science immunology 79 34797693
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
2012 TWEAK and cIAP1 regulate myoblast fusion through the noncanonical NF-κB signaling pathway. Science signaling 71 23074266
2017 TWEAK mediates inflammation in experimental atopic dermatitis and psoriasis. Nature communications 70 28530223
2013 TWEAK/Fn14 pathway modulates properties of a human microvascular endothelial cell model of blood brain barrier. Journal of neuroinflammation 67 23320797
2015 The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics. Oncogene 63 26300004
2024 Th17 Cells Secrete TWEAK to Trigger Epithelial-Mesenchymal Transition and Promote Colorectal Cancer Liver Metastasis. Cancer research 61 38335276
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
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
2017 TWEAK/Fn14 Activation Participates in Skin Inflammation. Mediators of inflammation 54 29038621
2009 Considering TWEAK as a target for therapy in renal and vascular injury. Cytokine & growth factor reviews 53 19482507
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
2021 Cross-talk between IFN-γ and TWEAK through miR-149 amplifies skin inflammation in psoriasis. The Journal of allergy and clinical immunology 50 33705829
2018 The lncRNA RHPN1-AS1 downregulation promotes gefitinib resistance by targeting miR-299-3p/TNFSF12 pathway in NSCLC. Cell cycle (Georgetown, Tex.) 50 30010468
2009 TWEAK promotes ovarian cancer cell metastasis via NF-kappaB pathway activation and VEGF expression. Cancer letters 50 19398263
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
2013 TWEAK transactivation of the epidermal growth factor receptor mediates renal inflammation. The Journal of pathology 47 24037740
2020 TWEAK/Fn14 axis is an important player in fibrosis. Journal of cellular physiology 45 33000480
2014 Role of the TWEAK-Fn14-cIAP1-NF-κB Signaling Axis in the Regulation of Myogenesis and Muscle Homeostasis. Frontiers in immunology 45 24550918
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
2017 TWEAK/Fn14 Activation Contributes to the Pathogenesis of Bullous Pemphigoid. The Journal of investigative dermatology 43 28351660
2007 TWEAK and the central nervous system. Molecular neurobiology 42 17917114
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
2012 TWEAK promotes the production of Interleukin-17 in rheumatoid arthritis. Cytokine 40 22819243
2011 TWEAK and Fn14 expression in the pathogenesis of joint inflammation and bone erosion in rheumatoid arthritis. Arthritis research & therapy 40 21435232
2013 TWEAK: A New Player in Obesity and Diabetes. Frontiers in immunology 39 24416031
2012 The TWEAK-Fn14 system: breaking the silence of cytokine-induced skeletal muscle wasting. Current molecular medicine 38 22082477
2005 Functional expression of TWEAK in human colonic adenocarcinoma cells. International journal of oncology 38 15586228
2014 Genetic deletion or TWEAK blocking antibody administration reduce atherosclerosis and enhance plaque stability in mice. Journal of cellular and molecular medicine 37 24479820
2018 TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cultured cardiac fibroblasts and the heart. Journal of molecular and cellular cardiology 36 29981796
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 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
2021 TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease. Journal of the American Society of Nephrology : JASN 34 34155062
2018 Involvement of TWEAK and the NF-κB signaling pathway in lupus nephritis. Experimental and therapeutic medicine 34 29456665
2013 Is TWEAK a Biomarker for Autoimmune/Chronic Inflammatory Diseases? Frontiers in immunology 34 24409182
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
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
2009 Therapeutic targeting of TWEAK/Fnl4 in cancer: exploiting the intrinsic tumor cell killing capacity of the pathway. Results and problems in cell differentiation 29 19513634
2003 TWE-PRIL; a fusion protein of TWEAK and APRIL. Biochemical pharmacology 28 14555217
2020 Controversies in TWEAK-Fn14 signaling in skeletal muscle atrophy and regeneration. Cellular and molecular life sciences : CMLS 27 32200423
2015 Serum levels of TWEAK in patients with psoriasis vulgaris. Cytokine 27 26499979
2014 TWEAK/Fn14 pathway is a novel mediator of retinal neovascularization. Investigative ophthalmology & visual science 27 24408972
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
2019 VPS29, a tweak tool of endosomal recycling. Current opinion in cell biology 25 31051431
2014 Nrf2 protects against TWEAK-mediated skeletal muscle wasting. Scientific reports 25 24406502
2005 TWEAK mediates anti-tumor effect of tumor-infiltrating macrophage. Biochemical and biophysical research communications 25 15850771
2023 TWEAK/FN14 promotes profibrogenic pathway activation in Prominin-1-expressing hepatic progenitor cells in biliary atresia. Hepatology (Baltimore, Md.) 24 36626628
2019 TRAIL, OPG, and TWEAK in kidney disease: biomarkers or therapeutic targets? Clinical science (London, England : 1979) 24 31097613
2007 Tweak and FN14 in central nervous system health and disease. Frontiers in bioscience : a journal and virtual library 23 17485258
2016 Tweak up-regulates endothelin-1 system in mouse and human endothelial cells. Cardiovascular research 22 28025386
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
2021 Bacterial effectors mimicking ubiquitin-proteasome pathway tweak plant immunity. Microbiological research 21 34246833
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
2016 TWEAK increases SIRT1 expression and promotes p53 deacetylation affecting human hepatic stellate cell senescence. Cell biology international 20 27888541

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