{"gene":"TNFSF14","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2008,"finding":"LIGHT (TNFSF14) activates two cell surface receptors: the Herpesvirus Entry Mediator (HVEM) and the Lymphotoxin-beta Receptor (LTβR), and is inhibited by soluble decoy receptor-3 (DcR3). HVEM also binds the Ig superfamily member BTLA, which inhibits T-cell activation, making HVEM a molecular switch between stimulatory and inhibitory signaling.","method":"Receptor binding studies, genetic and biochemical characterization described in review of experimental data","journal":"Immunological reviews","confidence":"High","confidence_rationale":"Tier 2 / Strong — findings replicated across multiple labs and confirmed by multiple orthogonal approaches including binding assays and in vivo models","pmids":["18613837","19760072"],"is_preprint":false},{"year":2014,"finding":"TNFSF14 (LIGHT) protein expression is rapidly induced in human NK cells by three mechanisms: CD16 engagement, synergistic activity of multiple NK-cell activation receptors, and IL-2/IL-15 cytokine stimulation. TNFSF14 is preferentially produced by licensed NK cells (defined by inhibitory receptors specific for self-MHC class I). Tumor- and cytokine-activated NK cells induced DC maturation in a TNFSF14-dependent manner, as shown by antibody blocking experiments.","method":"Gene expression profiling, TNFSF14 protein detection, antibody neutralization of TNFSF14-dependent DC maturation, NK cell activation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (gene expression, protein assay, neutralization), single lab but rigorous","pmids":["25512551"],"is_preprint":false},{"year":2018,"finding":"TNFSF14/LIGHT activates proinflammatory and remodeling activities in primary human lung fibroblasts (HLFs) including cell cycle progression, proliferation, upregulation of ICAM-1, VCAM-1, IL-6, GM-CSF, CCL5, CCL20, CXCL5/11/12, MMP-9, ADAM8, IL-33, and TSLP. These effects were dependent on LTβR but not HVEM signaling.","method":"Recombinant LIGHT treatment of primary HLFs, receptor-specific blocking, gene/protein expression analysis (ELISA, qPCR), proliferation assays","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays (proliferation, gene expression, protein secretion, receptor-specific inhibition), single lab","pmids":["29616048"],"is_preprint":false},{"year":2007,"finding":"Platelet-associated LIGHT (TNFSF14) mediates adhesion of platelets to human vascular endothelium under both static and dynamic flow conditions, and this interaction is inhibited by a monoclonal antibody to LIGHT. Soluble LIGHT stimulates endothelial cells to upregulate ICAM-1, tissue factor, and IL-8 via NFκB activation. LIGHT is expressed on platelets upon ADP or TRAP-1 activation, and its receptors TR2 and LTβR are expressed on human endothelial cells.","method":"FACS analysis of receptor expression, platelet adhesion assays (static and flow), antibody blockade, ICAM-1/TF/IL-8 expression measurement, NFκB activation assay","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (adhesion assay, flow conditions, antibody blockade, NFκB signaling), single lab","pmids":["17938804"],"is_preprint":false},{"year":2011,"finding":"Soluble LIGHT (sLIGHT) displays chemotactic activity for macrophages and T cells, and enhances inflammatory cytokine release from macrophages, adipocytes, and adipose tissue-derived stromal vascular fraction cells. These inflammatory responses were blunted by neutralizing anti-HVEM antibody or HVEM knockout, identifying HVEM as the receptor mediating LIGHT's adipose tissue inflammatory effects.","method":"Chemotaxis assays, cytokine measurement (ELISA), antibody neutralization, HVEM knockout cells","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (chemotaxis, cytokine ELISA, antibody neutralization, KO), single lab","pmids":["21236258"],"is_preprint":false},{"year":2014,"finding":"LIGHT (TNFSF14) induces osteoclastogenesis in both RANKL-dependent and RANKL-independent manners. In the presence of sub-optimal RANKL, LIGHT and RANKL synergistically stimulate osteoclast formation via phosphorylation of Akt, NFκB, and JNK pathways. LIGHT also inhibits osteoblastogenesis, partly through sclerostin expressed by monocytes.","method":"In vitro osteoclast/osteoblast differentiation cultures, signaling pathway analysis (western blot for phospho-Akt, NFκB, JNK), CFU-F and CFU-OB colony assays, osteoblastic marker expression","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (differentiation assays, signaling analysis, colony assays), single lab","pmids":["25460501"],"is_preprint":false},{"year":2018,"finding":"TNFSF14/LIGHT, acting as a non-canonical NF-κB stimulus, induces the HIF pathway specifically by upregulating HIF-2α transcription (but not HIF-1α) via a mechanism dependent on the p52 NF-κB subunit. p52 was shown to bind the HIF-2α promoter in cells.","method":"Reporter assays, western blot, qRT-PCR, chromatin immunoprecipitation (ChIP) for p52 binding to HIF-2α promoter","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (transcriptional analysis, ChIP), single lab but mechanistically specific","pmids":["30096845"],"is_preprint":false},{"year":2005,"finding":"Human melanoma cells constitutively express LIGHT/TNFSF14 intracellularly and on tumor-derived microvesicles. LIGHT+ melanoma-derived microvesicles costimulated LIGHT-dependent CD3+CD8+ T-cell proliferation in the presence of IL-2, but also induced apoptosis (increased Annexin V binding) of CD8+ T cells.","method":"Immunostaining, microvesicle isolation, co-culture assays, flow cytometry (Annexin V, T cell proliferation)","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple methods (immunostaining, co-culture, flow cytometry) but single lab without full mechanistic dissection","pmids":["15833878"],"is_preprint":false},{"year":2008,"finding":"LIGHT and its receptors HVEM and LTβR are upregulated in experimental heart failure (post-infarction rats) with strong expression in the infarcted area and HVEM upregulation in cardiomyocytes and endothelial cells. LIGHT induced IL-6 expression in endothelial cells in vitro; in HF patients (but not healthy controls), LIGHT-activated PBMCs also showed IL-6-inducing activity.","method":"Immunohistochemistry, in vitro endothelial cell stimulation, PBMC activation assays, IL-6 measurement","journal":"European journal of heart failure","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vitro mechanistic assays plus clinical and experimental model data, single lab","pmids":["18353719"],"is_preprint":false},{"year":2016,"finding":"LIGHT (TNFSF14) interaction with LTβR (constitutively expressed on human BM-MSCs) increases survival and proliferation of mesenchymal stem cells by upregulating cyclins B1, D1, D3, E and CDK1/CDK2, while decreasing p27, via PDGF and TGFβ production mediated by STAT3 and Smad3 activation.","method":"rhLIGHT treatment, cell viability/proliferation assays, cell cycle analysis, ELISA (PDGF, TGFβ), immunoblotting (cyclins, CDKs, p27, STAT3, Smad3)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple methods (cell cycle, ELISA, western blot), single lab","pmids":["27835685"],"is_preprint":false},{"year":2010,"finding":"Forced expression of LIGHT in tumors increases IFN-γ and chemoattractant cytokines (IL-1α, MIG, MIP-2) within the tumor, increases tumor-infiltrating CD8+ T cells, and expands functional T cells recognizing multiple tumor antigens including HPV16 E7. LIGHT expression establishes lymphoid-like tissue inside tumor sites and recruits naïve T cells.","method":"Adenoviral LIGHT overexpression in tumors, cytokine measurement, flow cytometry for TIL, T-cell functional assays, tumor challenge models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo tumor model with multiple readouts, single lab","pmids":["20460520"],"is_preprint":false},{"year":2019,"finding":"Genetic inactivation of LIGHT (Tnfsf14-/-) in mice fed a high-fat high-cholesterol diet improves glucose tolerance and insulin sensitivity, reduces hepatic inflammation and NAFLD activity score, and is associated with decreased hepatic Zbtb16, Klf6, and Tlr4 expression. HVEM and LTβR were markedly increased in livers of HFHCD-fed wild-type mice, indicating upregulated LIGHT signaling. LIGHT deficiency altered adipose tissue macrophage polarization (increased anti-inflammatory F4/80+CD206+ and decreased proinflammatory F4/80+CD11c+ macrophages).","method":"Tnfsf14-/- knockout mouse model, glucose tolerance and insulin sensitivity tests, histology (NAS scoring), flow cytometry, hepatic gene expression analysis","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple orthogonal physiological, histological, and molecular readouts, single lab but comprehensive","pmids":["31388695"],"is_preprint":false},{"year":2020,"finding":"In a mouse model of NSCLC bone metastasis (intratibial LLC-1 implantation), wild-type mice showed increased osteoclasts and reduced osteoblasts, while Tnfsf14-/- mice showed no significant bone loss or changes in bone homeostasis, demonstrating LIGHT is required for osteolytic bone metastasis-driven bone remodeling.","method":"Intratibial tumor implantation in WT and Tnfsf14-/- mice, histomorphometry, osteoclast/osteoblast counting, RANKL/anti-LIGHT blocking in PBMC cultures","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vivo bone phenotype and in vitro mechanistic validation, single lab","pmids":["31826304"],"is_preprint":false},{"year":2023,"finding":"LIGHT (TNFSF14) promotes cardiac fibrosis and atrial fibrillation vulnerability by promoting macrophage M2 polarization and TGF-β1 secretion via PI3Kγ/SGK1 pathway activation. Recombinant LIGHT treatment of bone marrow-derived macrophages activates PI3Kγ/SGK1, and conditioned medium from these macrophages increases collagen synthesis and myofibroblast transition in cardiac fibroblasts; both effects were inhibited by PI3Kγ and SGK1 inhibitors.","method":"In vivo rLIGHT injection in mice, in vitro BMDM stimulation, macrophage conditioned medium on cardiac fibroblasts, PI3Kγ/SGK1 inhibitors, RNA sequencing, atrial burst pacing for AF inducibility, MASSON staining","journal":"Journal of translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo model plus in vitro mechanistic pathway dissection with inhibitors and RNA-seq, single lab","pmids":["37580750"],"is_preprint":false},{"year":2023,"finding":"LIGHT (TNFSF14) co-expressed on CAR-T cells enhances cytotoxicity and cytokine production, promotes CCL19 and CCL21 expression in surrounding cells, and improves T cell migration in a paracrine manner. LIGHT CAR-T cells showed superior anti-tumor efficacy and improved intratumoral infiltration in NSG mice, and murine LIGHT-OT-1 T cells normalized tumor blood vessels and enforced intratumoral lymphoid structures in syngeneic tumor models.","method":"In vitro cytotoxicity assays, cytokine/chemokine measurement, T cell migration assays, xenograft (NSG) and syngeneic mouse tumor models","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo methods, single lab","pmids":["37408308"],"is_preprint":false},{"year":2019,"finding":"miR-326 targets TNFSF14 (as validated by molecular target identification experiments), and miR-326-mediated suppression of TNFSF14 dampens pulmonary inflammation in silica-induced fibrosis. TNFSF14 is identified as a direct downstream target of miR-326 controlling the inflammatory response.","method":"Luciferase reporter/target validation assay, miR-326 overexpression in mouse fibrosis model, western blot, immunofluorescence","journal":"Chemical research in toxicology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — target validation with reporter assay and in vivo model, but the mechanistic insight on TNFSF14 protein itself is indirect (post-transcriptional regulation), single lab","pmids":["31642316"],"is_preprint":false}],"current_model":"TNFSF14 (LIGHT) is a TNF superfamily cytokine that functions as a homotrimer signaling through two cell-surface receptors—HVEM and LTβR—to activate downstream pathways including NFκB (canonical and non-canonical), Akt, JNK, STAT3, Smad3, and PI3Kγ/SGK1, thereby promoting T-cell costimulation, DC maturation, osteoclastogenesis, fibroblast proliferation, macrophage polarization, endothelial activation, and tissue remodeling, while HVEM also serves as a molecular switch by binding the inhibitory adaptor BTLA to suppress T-cell activation."},"narrative":{"mechanistic_narrative":"TNFSF14 (LIGHT) is a TNF-superfamily cytokine that drives inflammation and tissue remodeling by signaling through two cell-surface receptors, HVEM and LTβR, with HVEM additionally functioning as a molecular switch through its interaction with the inhibitory adaptor BTLA to suppress T-cell activation [PMID:18613837, PMID:19760072]. Receptor choice partitions LIGHT's effects: LTβR mediates proinflammatory and remodeling activation of primary lung fibroblasts—proliferation and induction of adhesion molecules, cytokines, chemokines, and matrix-remodeling enzymes [PMID:29616048]—and supports survival and proliferation of mesenchymal stem cells via STAT3- and Smad3-dependent PDGF/TGFβ production [PMID:27835685], whereas HVEM transduces LIGHT's chemotactic and cytokine-inducing effects in macrophages and adipose tissue [PMID:21236258]. Downstream, LIGHT engages canonical and non-canonical NFκB, with the p52 subunit binding and transactivating the HIF-2α promoter [PMID:30096845], and activates Akt/JNK during osteoclastogenesis [PMID:25460501] and a PI3Kγ/SGK1 axis that polarizes macrophages toward TGF-β1 secretion [PMID:37580750]. Through these circuits LIGHT promotes endothelial activation and platelet adhesion [PMID:17938804], osteoclast formation and osteolytic bone remodeling [PMID:25460501, PMID:31826304], cardiac fibrosis [PMID:37580750], and hepatic/adipose metabolic inflammation, since Tnfsf14-deficient mice are protected from diet-induced glucose intolerance and NAFLD [PMID:31388695]. LIGHT is produced by activated NK cells to license dendritic-cell maturation [PMID:25512551] and, when forced into tumors or co-expressed on CAR-T cells, organizes intratumoral lymphoid structures, recruits and expands antigen-specific CD8+ T cells, and enhances anti-tumor efficacy [PMID:20460520, PMID:37408308].","teleology":[{"year":2008,"claim":"Established the core receptor architecture of LIGHT signaling—that it engages both HVEM and LTβR, is buffered by the soluble decoy DcR3, and that HVEM doubles as a stimulatory/inhibitory switch through BTLA—defining the receptor logic for all downstream biology.","evidence":"Receptor binding and biochemical/genetic characterization synthesized from experimental data","pmids":["18613837","19760072"],"confidence":"High","gaps":["Does not resolve which cell types preferentially use HVEM versus LTβR","Structural basis of the HVEM stimulatory/inhibitory switch not detailed"]},{"year":2007,"claim":"Showed LIGHT is a platelet-borne effector that bridges thrombosis and vascular inflammation, mediating platelet-endothelial adhesion and driving endothelial ICAM-1, tissue factor, and IL-8 via NFκB.","evidence":"Platelet adhesion under static/flow conditions, antibody blockade, and NFκB/expression assays in human endothelial cells","pmids":["17938804"],"confidence":"High","gaps":["Receptor (TR2/HVEM vs LTβR) responsible for endothelial activation not isolated","In vivo relevance to vascular disease not tested here"]},{"year":2010,"claim":"Demonstrated LIGHT can reprogram the tumor microenvironment, converting tumors into lymphoid-like tissue that recruits naive T cells and expands functional antigen-specific CD8+ responses, establishing its immunotherapeutic potential.","evidence":"Adenoviral LIGHT overexpression in tumors with cytokine, TIL, and T-cell functional readouts in mouse models","pmids":["20460520"],"confidence":"Medium","gaps":["Receptor mediating lymphoid neogenesis not pinned down","Single-lab in vivo model"]},{"year":2014,"claim":"Identified licensed NK cells as a physiological source of LIGHT and linked NK-derived LIGHT to dendritic-cell maturation, connecting innate activation to adaptive priming.","evidence":"Gene expression profiling, protein detection, and antibody neutralization of DC maturation in human NK-cell assays","pmids":["25512551"],"confidence":"High","gaps":["Receptor on DCs mediating maturation not defined","Whether membrane or soluble LIGHT drives the effect unresolved"]},{"year":2014,"claim":"Defined LIGHT as a regulator of bone homeostasis, driving osteoclastogenesis both with and independently of RANKL through Akt/NFκB/JNK while suppressing osteoblast formation.","evidence":"In vitro osteoclast/osteoblast differentiation and colony assays with phospho-signaling western blots","pmids":["25460501"],"confidence":"High","gaps":["Receptor specificity for osteoclast versus osteoblast effects not separated","Sclerostin-mediated osteoblast suppression mechanism incompletely mapped"]},{"year":2016,"claim":"Revealed an LTβR-dependent pro-survival/proliferative program in mesenchymal stem cells driven by STAT3 and Smad3 signaling and autocrine PDGF/TGFβ, broadening LIGHT's role beyond immune cells to stromal expansion.","evidence":"rhLIGHT treatment of BM-MSCs with cell-cycle analysis, ELISA, and immunoblotting","pmids":["27835685"],"confidence":"Medium","gaps":["Direct vs PDGF/TGFβ-indirect contributions to proliferation not separated","Single-lab study"]},{"year":2018,"claim":"Extended the fibroblast-activating role of LIGHT to the lung and assigned it specifically to LTβR rather than HVEM, identifying a remodeling/inflammatory gene program relevant to airway disease.","evidence":"Recombinant LIGHT on primary human lung fibroblasts with receptor-specific blockade and gene/protein expression assays","pmids":["29616048"],"confidence":"High","gaps":["In vivo contribution to fibrotic disease not addressed","Signaling intermediates downstream of LTβR not dissected"]},{"year":2018,"claim":"Connected LIGHT's non-canonical NFκB output to hypoxia signaling, showing the p52 subunit selectively transactivates HIF-2α by binding its promoter, providing a transcriptional mechanism for LIGHT-driven gene programs.","evidence":"Reporter assays, qRT-PCR, western blot, and ChIP for p52 binding to the HIF-2α promoter","pmids":["30096845"],"confidence":"Medium","gaps":["Physiological consequences of HIF-2α induction not tested","Selectivity for HIF-2α over HIF-1α mechanism incompletely explained"]},{"year":2019,"claim":"Genetic loss-of-function established LIGHT as a causal driver of metabolic inflammation, with Tnfsf14-/- mice protected from diet-induced glucose intolerance and NAFLD and showing a shift toward anti-inflammatory adipose macrophages.","evidence":"Tnfsf14-/- mice on high-fat high-cholesterol diet with metabolic, histological, and hepatic gene-expression readouts","pmids":["31388695"],"confidence":"High","gaps":["Cellular source of pathogenic LIGHT in metabolic tissue not identified","Receptor mediating the metabolic phenotype not isolated"]},{"year":2019,"claim":"Placed TNFSF14 under post-transcriptional control by miR-326, with miR-326-mediated suppression dampening silica-induced pulmonary inflammation, defining an upstream regulatory node.","evidence":"Luciferase target validation, miR-326 overexpression in a mouse fibrosis model, western blot and immunofluorescence","pmids":["31642316"],"confidence":"Medium","gaps":["Insight is on regulation of TNFSF14 rather than protein mechanism","Single-lab validation"]},{"year":2020,"claim":"Demonstrated that LIGHT is required for osteolytic bone metastasis, since Tnfsf14-/- mice resist tumor-driven bone loss, translating the in vitro osteoclastogenic role into a pathological in vivo requirement.","evidence":"Intratibial NSCLC implantation in WT vs Tnfsf14-/- mice with histomorphometry and PBMC blocking assays","pmids":["31826304"],"confidence":"High","gaps":["Tumor- vs host-derived LIGHT contribution not separated","Receptor driving metastatic osteolysis not defined"]},{"year":2023,"claim":"Defined a macrophage-to-fibroblast paracrine fibrotic circuit in which LIGHT activates PI3Kγ/SGK1 to drive M2 polarization and TGF-β1 secretion, promoting cardiac fibrosis and atrial fibrillation vulnerability.","evidence":"In vivo rLIGHT injection, BMDM stimulation, conditioned-medium transfer to cardiac fibroblasts with PI3Kγ/SGK1 inhibitors and RNA-seq","pmids":["37580750"],"confidence":"High","gaps":["Receptor coupling to PI3Kγ/SGK1 not specified","Direct fibroblast effects of LIGHT versus macrophage-mediated effects not fully separated"]},{"year":2023,"claim":"Showed that engineering LIGHT onto CAR-T cells enhances cytotoxicity, induces CCL19/CCL21 to recruit T cells, normalizes tumor vasculature, and improves anti-tumor efficacy, advancing LIGHT as a programmable immunotherapy module.","evidence":"In vitro cytotoxicity/chemokine/migration assays plus NSG xenograft and syngeneic mouse tumor models","pmids":["37408308"],"confidence":"Medium","gaps":["Receptor mediating chemokine induction and vascular normalization not isolated","Single-lab study"]},{"year":null,"claim":"How HVEM versus LTβR engagement, BTLA/DcR3 competition, and membrane versus soluble LIGHT are coordinated to select between stimulatory, inhibitory, and remodeling outcomes across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of context-dependent receptor selection","Cell-type-specific receptor usage in vivo largely uncharacterized","Quantitative role of DcR3 decoy buffering in disease not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,7]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[4]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,6,13]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[2,13]}],"complexes":[],"partners":["HVEM","LTBR","BTLA","DCR3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43557","full_name":"Tumor necrosis factor ligand superfamily member 14","aliases":["Herpes virus entry mediator ligand","HVEM-L","Herpesvirus entry mediator ligand"],"length_aa":240,"mass_kda":26.4,"function":"Cytokine that binds to TNFRSF3/LTBR. Binding to the decoy receptor TNFRSF6B modulates its effects. Acts as a ligand for TNFRSF14/HVEM (PubMed:10754304, PubMed:9462508). Upon binding to TNFRSF14/HVEM, delivers costimulatory signals to T cells, leading to T cell proliferation and IFNG production (PubMed:10754304)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O43557/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TNFSF14","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TNFSF14","total_profiled":1310},"omim":[{"mim_id":"619289","title":"ZINC FINGER PROTEIN 91, ATYPICAL E3 UBIQUITIN LIGASE; ZFP91","url":"https://www.omim.org/entry/619289"},{"mim_id":"607925","title":"B- AND T-LYMPHOCYTE ATTENUATOR; BTLA","url":"https://www.omim.org/entry/607925"},{"mim_id":"606945","title":"LOW DENSITY LIPOPROTEIN RECEPTOR; LDLR","url":"https://www.omim.org/entry/606945"},{"mim_id":"604520","title":"TUMOR NECROSIS FACTOR LIGAND SUPERFAMILY, MEMBER 14; TNFSF14","url":"https://www.omim.org/entry/604520"},{"mim_id":"602746","title":"TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY, MEMBER 14; TNFRSF14","url":"https://www.omim.org/entry/602746"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":24.3},{"tissue":"liver","ntpm":92.6}],"url":"https://www.proteinatlas.org/search/TNFSF14"},"hgnc":{"alias_symbol":["LIGHT","LTg","HVEM-L","CD258"],"prev_symbol":[]},"alphafold":{"accession":"O43557","domains":[{"cath_id":"2.60.120.40","chopping":"96-240","consensus_level":"high","plddt":94.5186,"start":96,"end":240},{"cath_id":"1.20.5","chopping":"37-75","consensus_level":"medium","plddt":84.6059,"start":37,"end":75}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43557","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43557-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43557-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TNFSF14","jax_strain_url":"https://www.jax.org/strain/search?query=TNFSF14"},"sequence":{"accession":"O43557","fasta_url":"https://rest.uniprot.org/uniprotkb/O43557.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43557/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43557"}},"corpus_meta":[{"pmid":"19575582","id":"PMC_19575582","title":"Sensing 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HVEM also binds the Ig superfamily member BTLA, which inhibits T-cell activation, making HVEM a molecular switch between stimulatory and inhibitory signaling.\",\n      \"method\": \"Receptor binding studies, genetic and biochemical characterization described in review of experimental data\",\n      \"journal\": \"Immunological reviews\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — findings replicated across multiple labs and confirmed by multiple orthogonal approaches including binding assays and in vivo models\",\n      \"pmids\": [\"18613837\", \"19760072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TNFSF14 (LIGHT) protein expression is rapidly induced in human NK cells by three mechanisms: CD16 engagement, synergistic activity of multiple NK-cell activation receptors, and IL-2/IL-15 cytokine stimulation. TNFSF14 is preferentially produced by licensed NK cells (defined by inhibitory receptors specific for self-MHC class I). Tumor- and cytokine-activated NK cells induced DC maturation in a TNFSF14-dependent manner, as shown by antibody blocking experiments.\",\n      \"method\": \"Gene expression profiling, TNFSF14 protein detection, antibody neutralization of TNFSF14-dependent DC maturation, NK cell activation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (gene expression, protein assay, neutralization), single lab but rigorous\",\n      \"pmids\": [\"25512551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TNFSF14/LIGHT activates proinflammatory and remodeling activities in primary human lung fibroblasts (HLFs) including cell cycle progression, proliferation, upregulation of ICAM-1, VCAM-1, IL-6, GM-CSF, CCL5, CCL20, CXCL5/11/12, MMP-9, ADAM8, IL-33, and TSLP. These effects were dependent on LTβR but not HVEM signaling.\",\n      \"method\": \"Recombinant LIGHT treatment of primary HLFs, receptor-specific blocking, gene/protein expression analysis (ELISA, qPCR), proliferation assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays (proliferation, gene expression, protein secretion, receptor-specific inhibition), single lab\",\n      \"pmids\": [\"29616048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Platelet-associated LIGHT (TNFSF14) mediates adhesion of platelets to human vascular endothelium under both static and dynamic flow conditions, and this interaction is inhibited by a monoclonal antibody to LIGHT. Soluble LIGHT stimulates endothelial cells to upregulate ICAM-1, tissue factor, and IL-8 via NFκB activation. LIGHT is expressed on platelets upon ADP or TRAP-1 activation, and its receptors TR2 and LTβR are expressed on human endothelial cells.\",\n      \"method\": \"FACS analysis of receptor expression, platelet adhesion assays (static and flow), antibody blockade, ICAM-1/TF/IL-8 expression measurement, NFκB activation assay\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (adhesion assay, flow conditions, antibody blockade, NFκB signaling), single lab\",\n      \"pmids\": [\"17938804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Soluble LIGHT (sLIGHT) displays chemotactic activity for macrophages and T cells, and enhances inflammatory cytokine release from macrophages, adipocytes, and adipose tissue-derived stromal vascular fraction cells. These inflammatory responses were blunted by neutralizing anti-HVEM antibody or HVEM knockout, identifying HVEM as the receptor mediating LIGHT's adipose tissue inflammatory effects.\",\n      \"method\": \"Chemotaxis assays, cytokine measurement (ELISA), antibody neutralization, HVEM knockout cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (chemotaxis, cytokine ELISA, antibody neutralization, KO), single lab\",\n      \"pmids\": [\"21236258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LIGHT (TNFSF14) induces osteoclastogenesis in both RANKL-dependent and RANKL-independent manners. In the presence of sub-optimal RANKL, LIGHT and RANKL synergistically stimulate osteoclast formation via phosphorylation of Akt, NFκB, and JNK pathways. LIGHT also inhibits osteoblastogenesis, partly through sclerostin expressed by monocytes.\",\n      \"method\": \"In vitro osteoclast/osteoblast differentiation cultures, signaling pathway analysis (western blot for phospho-Akt, NFκB, JNK), CFU-F and CFU-OB colony assays, osteoblastic marker expression\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (differentiation assays, signaling analysis, colony assays), single lab\",\n      \"pmids\": [\"25460501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TNFSF14/LIGHT, acting as a non-canonical NF-κB stimulus, induces the HIF pathway specifically by upregulating HIF-2α transcription (but not HIF-1α) via a mechanism dependent on the p52 NF-κB subunit. p52 was shown to bind the HIF-2α promoter in cells.\",\n      \"method\": \"Reporter assays, western blot, qRT-PCR, chromatin immunoprecipitation (ChIP) for p52 binding to HIF-2α promoter\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (transcriptional analysis, ChIP), single lab but mechanistically specific\",\n      \"pmids\": [\"30096845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human melanoma cells constitutively express LIGHT/TNFSF14 intracellularly and on tumor-derived microvesicles. LIGHT+ melanoma-derived microvesicles costimulated LIGHT-dependent CD3+CD8+ T-cell proliferation in the presence of IL-2, but also induced apoptosis (increased Annexin V binding) of CD8+ T cells.\",\n      \"method\": \"Immunostaining, microvesicle isolation, co-culture assays, flow cytometry (Annexin V, T cell proliferation)\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple methods (immunostaining, co-culture, flow cytometry) but single lab without full mechanistic dissection\",\n      \"pmids\": [\"15833878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LIGHT and its receptors HVEM and LTβR are upregulated in experimental heart failure (post-infarction rats) with strong expression in the infarcted area and HVEM upregulation in cardiomyocytes and endothelial cells. LIGHT induced IL-6 expression in endothelial cells in vitro; in HF patients (but not healthy controls), LIGHT-activated PBMCs also showed IL-6-inducing activity.\",\n      \"method\": \"Immunohistochemistry, in vitro endothelial cell stimulation, PBMC activation assays, IL-6 measurement\",\n      \"journal\": \"European journal of heart failure\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vitro mechanistic assays plus clinical and experimental model data, single lab\",\n      \"pmids\": [\"18353719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LIGHT (TNFSF14) interaction with LTβR (constitutively expressed on human BM-MSCs) increases survival and proliferation of mesenchymal stem cells by upregulating cyclins B1, D1, D3, E and CDK1/CDK2, while decreasing p27, via PDGF and TGFβ production mediated by STAT3 and Smad3 activation.\",\n      \"method\": \"rhLIGHT treatment, cell viability/proliferation assays, cell cycle analysis, ELISA (PDGF, TGFβ), immunoblotting (cyclins, CDKs, p27, STAT3, Smad3)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple methods (cell cycle, ELISA, western blot), single lab\",\n      \"pmids\": [\"27835685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Forced expression of LIGHT in tumors increases IFN-γ and chemoattractant cytokines (IL-1α, MIG, MIP-2) within the tumor, increases tumor-infiltrating CD8+ T cells, and expands functional T cells recognizing multiple tumor antigens including HPV16 E7. LIGHT expression establishes lymphoid-like tissue inside tumor sites and recruits naïve T cells.\",\n      \"method\": \"Adenoviral LIGHT overexpression in tumors, cytokine measurement, flow cytometry for TIL, T-cell functional assays, tumor challenge models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo tumor model with multiple readouts, single lab\",\n      \"pmids\": [\"20460520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Genetic inactivation of LIGHT (Tnfsf14-/-) in mice fed a high-fat high-cholesterol diet improves glucose tolerance and insulin sensitivity, reduces hepatic inflammation and NAFLD activity score, and is associated with decreased hepatic Zbtb16, Klf6, and Tlr4 expression. HVEM and LTβR were markedly increased in livers of HFHCD-fed wild-type mice, indicating upregulated LIGHT signaling. LIGHT deficiency altered adipose tissue macrophage polarization (increased anti-inflammatory F4/80+CD206+ and decreased proinflammatory F4/80+CD11c+ macrophages).\",\n      \"method\": \"Tnfsf14-/- knockout mouse model, glucose tolerance and insulin sensitivity tests, histology (NAS scoring), flow cytometry, hepatic gene expression analysis\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple orthogonal physiological, histological, and molecular readouts, single lab but comprehensive\",\n      \"pmids\": [\"31388695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In a mouse model of NSCLC bone metastasis (intratibial LLC-1 implantation), wild-type mice showed increased osteoclasts and reduced osteoblasts, while Tnfsf14-/- mice showed no significant bone loss or changes in bone homeostasis, demonstrating LIGHT is required for osteolytic bone metastasis-driven bone remodeling.\",\n      \"method\": \"Intratibial tumor implantation in WT and Tnfsf14-/- mice, histomorphometry, osteoclast/osteoblast counting, RANKL/anti-LIGHT blocking in PBMC cultures\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vivo bone phenotype and in vitro mechanistic validation, single lab\",\n      \"pmids\": [\"31826304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LIGHT (TNFSF14) promotes cardiac fibrosis and atrial fibrillation vulnerability by promoting macrophage M2 polarization and TGF-β1 secretion via PI3Kγ/SGK1 pathway activation. Recombinant LIGHT treatment of bone marrow-derived macrophages activates PI3Kγ/SGK1, and conditioned medium from these macrophages increases collagen synthesis and myofibroblast transition in cardiac fibroblasts; both effects were inhibited by PI3Kγ and SGK1 inhibitors.\",\n      \"method\": \"In vivo rLIGHT injection in mice, in vitro BMDM stimulation, macrophage conditioned medium on cardiac fibroblasts, PI3Kγ/SGK1 inhibitors, RNA sequencing, atrial burst pacing for AF inducibility, MASSON staining\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model plus in vitro mechanistic pathway dissection with inhibitors and RNA-seq, single lab\",\n      \"pmids\": [\"37580750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LIGHT (TNFSF14) co-expressed on CAR-T cells enhances cytotoxicity and cytokine production, promotes CCL19 and CCL21 expression in surrounding cells, and improves T cell migration in a paracrine manner. LIGHT CAR-T cells showed superior anti-tumor efficacy and improved intratumoral infiltration in NSG mice, and murine LIGHT-OT-1 T cells normalized tumor blood vessels and enforced intratumoral lymphoid structures in syngeneic tumor models.\",\n      \"method\": \"In vitro cytotoxicity assays, cytokine/chemokine measurement, T cell migration assays, xenograft (NSG) and syngeneic mouse tumor models\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo methods, single lab\",\n      \"pmids\": [\"37408308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-326 targets TNFSF14 (as validated by molecular target identification experiments), and miR-326-mediated suppression of TNFSF14 dampens pulmonary inflammation in silica-induced fibrosis. TNFSF14 is identified as a direct downstream target of miR-326 controlling the inflammatory response.\",\n      \"method\": \"Luciferase reporter/target validation assay, miR-326 overexpression in mouse fibrosis model, western blot, immunofluorescence\",\n      \"journal\": \"Chemical research in toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — target validation with reporter assay and in vivo model, but the mechanistic insight on TNFSF14 protein itself is indirect (post-transcriptional regulation), single lab\",\n      \"pmids\": [\"31642316\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TNFSF14 (LIGHT) is a TNF superfamily cytokine that functions as a homotrimer signaling through two cell-surface receptors—HVEM and LTβR—to activate downstream pathways including NFκB (canonical and non-canonical), Akt, JNK, STAT3, Smad3, and PI3Kγ/SGK1, thereby promoting T-cell costimulation, DC maturation, osteoclastogenesis, fibroblast proliferation, macrophage polarization, endothelial activation, and tissue remodeling, while HVEM also serves as a molecular switch by binding the inhibitory adaptor BTLA to suppress T-cell activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TNFSF14 (LIGHT) is a TNF-superfamily cytokine that drives inflammation and tissue remodeling by signaling through two cell-surface receptors, HVEM and LT\\u03b2R, with HVEM additionally functioning as a molecular switch through its interaction with the inhibitory adaptor BTLA to suppress T-cell activation [#0]. Receptor choice partitions LIGHT's effects: LT\\u03b2R mediates proinflammatory and remodeling activation of primary lung fibroblasts\\u2014proliferation and induction of adhesion molecules, cytokines, chemokines, and matrix-remodeling enzymes [#2]\\u2014and supports survival and proliferation of mesenchymal stem cells via STAT3- and Smad3-dependent PDGF/TGF\\u03b2 production [#9], whereas HVEM transduces LIGHT's chemotactic and cytokine-inducing effects in macrophages and adipose tissue [#4]. Downstream, LIGHT engages canonical and non-canonical NF\\u03baB, with the p52 subunit binding and transactivating the HIF-2\\u03b1 promoter [#6], and activates Akt/JNK during osteoclastogenesis [#5] and a PI3K\\u03b3/SGK1 axis that polarizes macrophages toward TGF-\\u03b21 secretion [#13]. Through these circuits LIGHT promotes endothelial activation and platelet adhesion [#3], osteoclast formation and osteolytic bone remodeling [#5, #12], cardiac fibrosis [#13], and hepatic/adipose metabolic inflammation, since Tnfsf14-deficient mice are protected from diet-induced glucose intolerance and NAFLD [#11]. LIGHT is produced by activated NK cells to license dendritic-cell maturation [#1] and, when forced into tumors or co-expressed on CAR-T cells, organizes intratumoral lymphoid structures, recruits and expands antigen-specific CD8+ T cells, and enhances anti-tumor efficacy [#10, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established the core receptor architecture of LIGHT signaling\\u2014that it engages both HVEM and LT\\u03b2R, is buffered by the soluble decoy DcR3, and that HVEM doubles as a stimulatory/inhibitory switch through BTLA\\u2014defining the receptor logic for all downstream biology.\",\n      \"evidence\": \"Receptor binding and biochemical/genetic characterization synthesized from experimental data\",\n      \"pmids\": [\"18613837\", \"19760072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve which cell types preferentially use HVEM versus LT\\u03b2R\", \"Structural basis of the HVEM stimulatory/inhibitory switch not detailed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed LIGHT is a platelet-borne effector that bridges thrombosis and vascular inflammation, mediating platelet-endothelial adhesion and driving endothelial ICAM-1, tissue factor, and IL-8 via NF\\u03baB.\",\n      \"evidence\": \"Platelet adhesion under static/flow conditions, antibody blockade, and NF\\u03baB/expression assays in human endothelial cells\",\n      \"pmids\": [\"17938804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor (TR2/HVEM vs LT\\u03b2R) responsible for endothelial activation not isolated\", \"In vivo relevance to vascular disease not tested here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated LIGHT can reprogram the tumor microenvironment, converting tumors into lymphoid-like tissue that recruits naive T cells and expands functional antigen-specific CD8+ responses, establishing its immunotherapeutic potential.\",\n      \"evidence\": \"Adenoviral LIGHT overexpression in tumors with cytokine, TIL, and T-cell functional readouts in mouse models\",\n      \"pmids\": [\"20460520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating lymphoid neogenesis not pinned down\", \"Single-lab in vivo model\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified licensed NK cells as a physiological source of LIGHT and linked NK-derived LIGHT to dendritic-cell maturation, connecting innate activation to adaptive priming.\",\n      \"evidence\": \"Gene expression profiling, protein detection, and antibody neutralization of DC maturation in human NK-cell assays\",\n      \"pmids\": [\"25512551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor on DCs mediating maturation not defined\", \"Whether membrane or soluble LIGHT drives the effect unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined LIGHT as a regulator of bone homeostasis, driving osteoclastogenesis both with and independently of RANKL through Akt/NF\\u03baB/JNK while suppressing osteoblast formation.\",\n      \"evidence\": \"In vitro osteoclast/osteoblast differentiation and colony assays with phospho-signaling western blots\",\n      \"pmids\": [\"25460501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor specificity for osteoclast versus osteoblast effects not separated\", \"Sclerostin-mediated osteoblast suppression mechanism incompletely mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed an LT\\u03b2R-dependent pro-survival/proliferative program in mesenchymal stem cells driven by STAT3 and Smad3 signaling and autocrine PDGF/TGF\\u03b2, broadening LIGHT's role beyond immune cells to stromal expansion.\",\n      \"evidence\": \"rhLIGHT treatment of BM-MSCs with cell-cycle analysis, ELISA, and immunoblotting\",\n      \"pmids\": [\"27835685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs PDGF/TGF\\u03b2-indirect contributions to proliferation not separated\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the fibroblast-activating role of LIGHT to the lung and assigned it specifically to LT\\u03b2R rather than HVEM, identifying a remodeling/inflammatory gene program relevant to airway disease.\",\n      \"evidence\": \"Recombinant LIGHT on primary human lung fibroblasts with receptor-specific blockade and gene/protein expression assays\",\n      \"pmids\": [\"29616048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution to fibrotic disease not addressed\", \"Signaling intermediates downstream of LT\\u03b2R not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected LIGHT's non-canonical NF\\u03baB output to hypoxia signaling, showing the p52 subunit selectively transactivates HIF-2\\u03b1 by binding its promoter, providing a transcriptional mechanism for LIGHT-driven gene programs.\",\n      \"evidence\": \"Reporter assays, qRT-PCR, western blot, and ChIP for p52 binding to the HIF-2\\u03b1 promoter\",\n      \"pmids\": [\"30096845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological consequences of HIF-2\\u03b1 induction not tested\", \"Selectivity for HIF-2\\u03b1 over HIF-1\\u03b1 mechanism incompletely explained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genetic loss-of-function established LIGHT as a causal driver of metabolic inflammation, with Tnfsf14-/- mice protected from diet-induced glucose intolerance and NAFLD and showing a shift toward anti-inflammatory adipose macrophages.\",\n      \"evidence\": \"Tnfsf14-/- mice on high-fat high-cholesterol diet with metabolic, histological, and hepatic gene-expression readouts\",\n      \"pmids\": [\"31388695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular source of pathogenic LIGHT in metabolic tissue not identified\", \"Receptor mediating the metabolic phenotype not isolated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed TNFSF14 under post-transcriptional control by miR-326, with miR-326-mediated suppression dampening silica-induced pulmonary inflammation, defining an upstream regulatory node.\",\n      \"evidence\": \"Luciferase target validation, miR-326 overexpression in a mouse fibrosis model, western blot and immunofluorescence\",\n      \"pmids\": [\"31642316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Insight is on regulation of TNFSF14 rather than protein mechanism\", \"Single-lab validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that LIGHT is required for osteolytic bone metastasis, since Tnfsf14-/- mice resist tumor-driven bone loss, translating the in vitro osteoclastogenic role into a pathological in vivo requirement.\",\n      \"evidence\": \"Intratibial NSCLC implantation in WT vs Tnfsf14-/- mice with histomorphometry and PBMC blocking assays\",\n      \"pmids\": [\"31826304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tumor- vs host-derived LIGHT contribution not separated\", \"Receptor driving metastatic osteolysis not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a macrophage-to-fibroblast paracrine fibrotic circuit in which LIGHT activates PI3K\\u03b3/SGK1 to drive M2 polarization and TGF-\\u03b21 secretion, promoting cardiac fibrosis and atrial fibrillation vulnerability.\",\n      \"evidence\": \"In vivo rLIGHT injection, BMDM stimulation, conditioned-medium transfer to cardiac fibroblasts with PI3K\\u03b3/SGK1 inhibitors and RNA-seq\",\n      \"pmids\": [\"37580750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor coupling to PI3K\\u03b3/SGK1 not specified\", \"Direct fibroblast effects of LIGHT versus macrophage-mediated effects not fully separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed that engineering LIGHT onto CAR-T cells enhances cytotoxicity, induces CCL19/CCL21 to recruit T cells, normalizes tumor vasculature, and improves anti-tumor efficacy, advancing LIGHT as a programmable immunotherapy module.\",\n      \"evidence\": \"In vitro cytotoxicity/chemokine/migration assays plus NSG xenograft and syngeneic mouse tumor models\",\n      \"pmids\": [\"37408308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating chemokine induction and vascular normalization not isolated\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HVEM versus LT\\u03b2R engagement, BTLA/DcR3 competition, and membrane versus soluble LIGHT are coordinated to select between stimulatory, inhibitory, and remodeling outcomes across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of context-dependent receptor selection\", \"Cell-type-specific receptor usage in vivo largely uncharacterized\", \"Quantitative role of DcR3 decoy buffering in disease not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005102\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 6, 13]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HVEM\", \"LTBR\", \"BTLA\", \"DcR3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}