{"gene":"FGL1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1993,"finding":"FGL1 (HFREP-1) was identified as a novel fibrinogen-related protein specifically expressed in liver and hepatocellular carcinoma. The deduced protein sequence contained a hydrophobic leader peptide and showed marked homology with beta- and gamma-subunits of fibrinogen, but lacked a platelet-binding site, cross-linking region, and thrombin-sensitive site, indicating it cannot form fibrin clots.","method":"Subtractive/differential cDNA cloning, sequence analysis, Northern blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — original cloning paper with sequence analysis and tissue expression, single lab but foundational characterization","pmids":["8390249"],"is_preprint":false},{"year":2004,"finding":"LFIRE-1/HFREP-1 (FGL1) encodes a growth suppressor in hepatocellular carcinoma. Restoration of wild-type FGL1 expression in HCC cells inhibited anchorage-dependent and -independent growth in vitro and suppressed tumorigenicity in nude mice, whereas FGL1 missense mutations failed to do so. Antisense-mediated reduction of FGL1 enhanced cancer cell proliferation and colony formation.","method":"Exogenous gene restoration, antisense knockdown, colony formation assay, soft agar assay, nude mouse xenograft","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (gain-of-function, loss-of-function, in vivo), mutation analysis showing domain dependence, replicated across assays","pmids":["14981537"],"is_preprint":false},{"year":2016,"finding":"FGL1 forms disulfide-linked oligomers with FGL2 in the epididymis. These oligomers (eFGL) specifically bind nonviable spermatozoa in the cauda epididymidis. Co-immunoprecipitation using anti-FGL2 antibody demonstrated that both FGL1 and FGL2 are present in the soluble eFGL complex. FGL1 is expressed in principal cells of the proximal cauda epididymidis.","method":"Proteomics (LC-MS), PCR-based cloning, co-immunoprecipitation, immunocytochemistry, Northern blot, in situ hybridization","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteomics, co-IP, localization), single lab","pmids":["27732889"],"is_preprint":false},{"year":2020,"finding":"FGL1 confers acquired resistance to gefitinib in NSCLC by regulating the PARP1/caspase-3 apoptosis pathway. FGL1 knockdown suppressed cell viability, reduced gefitinib IC50, and enhanced apoptosis in PC9/GR cells; mechanistically, FGL1 inhibition reduced PARP1 and caspase-3 expression upon gefitinib treatment.","method":"siRNA knockdown, CCK-8 assay, colony formation, flow cytometry, Western blot, mouse xenograft, immunohistochemistry","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo knockdown with pathway readout, single lab, multiple orthogonal methods","pmids":["32778129"],"is_preprint":false},{"year":2020,"finding":"Oxysophocarpine sensitized LAG-3 immunotherapy against HCC by decreasing FGL1 expression through downregulation of IL-6-mediated JAK2/STAT3 signaling. This effect was specific to the LAG-3 pathway, as oxysophocarpine had little effect on CD8+ T cell cytotoxicity with PD-1, Tim-3, or TIGIT blockade.","method":"In vitro cell assays, in vivo subcutaneous tumor model, Western blot, flow cytometry","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments with pathway specificity controls, single lab","pmids":["32810392"],"is_preprint":false},{"year":2021,"finding":"FGL1 is a major functional ligand of the immune checkpoint receptor LAG-3 (lymphocyte activation gene 3). FGL1 binding to LAG-3 on T cells inhibits T cell activation and cytokine secretion. The D1-D2 domains of LAG-3 and the fibrinogen domain (FD) of FGL1 mediate this interaction.","method":"Binding assays, functional T cell co-culture assays (referenced across multiple papers as established finding)","journal":"Journal of hematology & oncology","confidence":"High","confidence_rationale":"Tier 2 / Strong — interaction and functional consequence independently replicated across multiple labs and multiple experimental systems","pmids":["34526102","35111155"],"is_preprint":false},{"year":2021,"finding":"Glucosyl-galactosyl-hydroxylation (GGH) post-translational modification occurs at Lys65 of FGL1, despite FGL1 lacking a collagen-like domain. This modification is carried out by the glycosyltransferases LH3 and GLT25D1. Knockout of LH3 or GLT25D1 significantly inhibited glycosylation, and deficiency of GGH (via point mutation or glycosyltransferase knockout) reduced FGL1 protein levels.","method":"LC-MS/MS analysis, LH3/GLT25D1-knockout cell lines (CRISPR), site-directed mutagenesis, Western blot","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro mass spectrometry identification of PTM site, confirmed by mutagenesis and knockout cell lines, multiple orthogonal approaches in single rigorous study","pmids":["33984770"],"is_preprint":false},{"year":2021,"finding":"FGL1 promotes proliferation of lung adenocarcinoma (LUAD) cells in vitro and in vivo, and is transcriptionally regulated by the transcription factor YY1. FGL1 directly binds MYH9 (identified by immunoprecipitation and mass spectrometry) to promote LUAD cell proliferation.","method":"Immunoprecipitation, mass spectrometry, chromatin immunoprecipitation, dual luciferase reporter assay, in vitro and in vivo proliferation assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS for binding partner, ChIP and luciferase for transcription factor, single lab with multiple orthogonal methods","pmids":["36268014"],"is_preprint":false},{"year":2023,"finding":"FBXO38, an E3 ubiquitin ligase, directly interacts with FGL1 and ubiquitylates it to promote its proteasomal degradation. Depletion of FBXO38 markedly augments FGL1 protein abundance, suppressing CD8+ T cell infiltration and enhancing tumor immune evasion.","method":"Co-immunoprecipitation, ubiquitination assay, FBXO38 knockout/knockdown, flow cytometry, Western blot","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct ubiquitination assay with E3 ligase identification, Co-IP for interaction, functional cellular readout, multiple methods in single rigorous study","pmids":["37938970"],"is_preprint":false},{"year":2023,"finding":"Tumor-associated macrophages (TAMs) activate NF-κB by secreting TNFα/IL-1β in the liver microenvironment, which transcriptionally upregulates OTUD1 (a deubiquitinase). OTUD1 then enhances FGL1 protein stability via deubiquitination, promoting metastatic tumor progression.","method":"Mechanistic experiments in intraportal injection model, Western blot, ubiquitination assay, NF-κB reporter assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — deubiquitination mechanism established with in vivo model, multiple orthogonal methods, published in high-impact journal","pmids":["37872170"],"is_preprint":false},{"year":2024,"finding":"FGL1 is a potent suppressor of hepcidin synthesis. FGL1 exerts this activity by directly binding to BMP6, thereby inhibiting the canonical BMP-SMAD signaling cascade that controls hepcidin transcription. Deletion of Fgl1 in mice results in higher hepcidin levels at baseline and after bleeding, and FGL1 is induced in the liver in response to hypoxia during anemia recovery.","method":"Fgl1 knockout mice, in vitro binding assays (BMP6 binding), hepcidin quantification in vitro and in vivo, BMP-SMAD pathway analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding demonstrated in vitro, genetic KO in vivo with pathway readout, published in peer-reviewed high-impact journal with complementary preprint data","pmids":["38232308"],"is_preprint":false},{"year":2024,"finding":"HDAC1 deacetylates JAK1; SAHA (HDACi) inhibits HDAC1, increasing acetylation of JAK1 at lysine 1109, promoting its proteasomal degradation and reducing STAT3-driven FGL1 transcription. This mechanism underlies SAHA-mediated suppression of FGL1 and enhancement of CD8+ T cell antitumor activity in lung adenocarcinoma.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, mass spectrometry, RNA sequencing, Western blot, ELISA, in vitro co-culture, in vivo tumor models","journal":"Journal for immunotherapy of cancer","confidence":"High","confidence_rationale":"Tier 1 / Moderate — acetylation site identified by mass spectrometry, ChIP for transcriptional regulation, in vitro and in vivo functional validation, multiple orthogonal methods","pmids":["39384195"],"is_preprint":false},{"year":2024,"finding":"USP7 deubiquitinates the transcription factor PRDM1, stabilizing it. PRDM1 then transcriptionally activates FGL1 expression in liver cancer cells, attenuating CD8+ T cell activity. A positive feedback loop exists in which PRDM1 also transcriptionally stimulates USP7.","method":"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, chromatin immunoprecipitation, in vivo xenograft, flow cytometry","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and deubiquitination assay demonstrate mechanism, ChIP for transcriptional regulation, functional validation in vivo, single lab","pmids":["38589688"],"is_preprint":false},{"year":2024,"finding":"PRMT5 catalyzes symmetric dimethylation of transcription factor TCF12 at arginine 554 (R554), promoting TCF12 binding to the FGL1 promoter and transcriptionally activating FGL1 in liver cancer cells. Methylation-deficient TCF12-R554 mutants fail to activate FGL1 transcription, and PRMT5 inhibition reduces FGL1 and enhances CD8+ T cell antitumor immunity.","method":"In vitro methylation assay, site-directed mutagenesis, chromatin immunoprecipitation, luciferase reporter assay, in vivo tumor models, flow cytometry","journal":"Acta pharmaceutica Sinica. B","confidence":"High","confidence_rationale":"Tier 1 / Moderate — enzymatic methylation at specific residue identified, mutagenesis validation, ChIP and luciferase for transcriptional mechanism, in vivo functional readout","pmids":["40041915"],"is_preprint":false},{"year":2024,"finding":"KDM4A interacts with STAT3 and facilitates removal of methyl groups from H3K9me3 at the FGL1 promoter, enhancing STAT3-mediated transcription of FGL1 in NSCLC cells. STAT3 acts as a direct transcription factor for FGL1 by binding its promoter.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, FGL1 promoter activity assay, Western blot, cell proliferation/migration assays","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for KDM4A-STAT3 interaction, ChIP for promoter occupancy, functional validation, single lab","pmids":["39085849"],"is_preprint":false},{"year":2024,"finding":"KRAS activates ERK1/2, which phosphorylates SET1A histone methyltransferase, increasing its stability and nuclear localization. SET1A-mediated methylation of Yap promotes its nuclear sequestration, driving Yap-induced transcription of FGL1 to promote immune evasion in KRAS-driven lung adenocarcinoma.","method":"Chromatin immunoprecipitation, dual luciferase reporter assay, lentiviral overexpression/silencing, flow cytometry, immunofluorescence, in vivo mouse models","journal":"Cancer communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase for transcriptional mechanism, multiple pathway components validated, single lab","pmids":["39340215"],"is_preprint":false},{"year":2024,"finding":"Hepatocyte-derived FGL1 directly inhibits hepatic CD8+ T and NK cell functions via the receptor LAG-3 in the liver microenvironment. Fgl1-deficient mice showed increased hepatic CD8+ T and NK cell numbers and functions, and anti-FGL1 mAb blockade restrained liver metastasis. The antitumor efficacy of FGL1 blockade was dependent on cytotoxic T lymphocytes and NK cells as demonstrated by cell-deficient models and cell transfer in vivo.","method":"Fgl1 knockout mice, anti-FGL1 mAb treatment, in vitro inhibition assays with LAG-3, cell depletion models, adoptive cell transfer, flow cytometry","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and antibody blockade converge on same phenotype, in vitro direct inhibition via LAG-3 confirmed, cell depletion experiments establish mechanism, multiple orthogonal approaches","pmids":["38973608"],"is_preprint":false},{"year":2024,"finding":"TRIM21 (an E3 ubiquitin ligase) targets FGL1 for proteasomal degradation, and this process is transcriptionally regulated by IRF1 (which activates TRIM21 transcription). Artemisinin upregulates the IRF1-TRIM21 axis, promoting FGL1 degradation and enhancing antitumor CTL activity.","method":"Western blot, ubiquitination assay, luciferase reporter assay, chromatin immunoprecipitation, in vivo tumor models, flow cytometry","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay demonstrates E3 ligase mechanism, ChIP and luciferase for transcriptional regulation, functional in vivo validation, single lab","pmids":["42020516"],"is_preprint":false},{"year":2024,"finding":"CENPM physically interacts with FGL1 in adrenocortical carcinoma cells, as demonstrated by co-immunoprecipitation and DIA quantitative proteomics. Overexpression of FGL1 rescued migration and invasion of CENPM knockdown ACC cells, placing FGL1 downstream of CENPM in ACC metastasis.","method":"DIA quantitative proteomics, co-immunoprecipitation, immunofluorescence, Western blot, migration/invasion assays, xenograft model","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with proteomics for binding partner, rescue experiments for epistasis, single lab","pmids":["39778025"],"is_preprint":false},{"year":2024,"finding":"FGL1 secreted from cancer-associated fibroblast (CAF)-derived exosomes interacts with SOX5 in prostate cancer cells and negatively regulates SOX5 expression, promoting PC cell viability, migration, and invasion via the FGL1/SOX5 axis.","method":"Co-immunoprecipitation, FISH, CCK-8, Transwell assay, rescue experiments, in vivo tumor model","journal":"Histology and histopathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for interaction, single lab, limited functional validation","pmids":["39463328"],"is_preprint":false},{"year":2024,"finding":"Radiation-induced upregulation of FGL1 in esophageal squamous cell carcinoma is mediated by the transcription factor FOXO4. FGL1 promotes ESCC metastasis through upregulation of IMPDH1; IMPDH1 knockdown reversed the pro-invasive effects of FGL1.","method":"qRT-PCR, Western blot, immunofluorescence, Transwell assay, wound healing, RNA sequencing, nude mouse models, rescue experiments","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiments establish epistasis (FGL1→IMPDH1), multiple assays, single lab","pmids":["38702629"],"is_preprint":false},{"year":2023,"finding":"FGL1 binding to LAG3 inhibits Treg cell proliferation and impairs the suppressive activity of Treg cells by limiting IL-10 secretion, and promotes pathogenic IL-17a and IL-21 production by CD4+ T cells. FGL1 expression in hepatocytes is induced by the inflammatory cytokine IL-6 signaling.","method":"Flow cytometry, ELISA, cell culture assays with functional antibody blockade, hepatocyte stimulation with cytokines","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blockade experiment defines LAG3-mediated Treg suppression mechanism, IL-6-induced FGL1 in hepatocytes confirmed in vitro, single lab","pmids":["37916085"],"is_preprint":false},{"year":2025,"finding":"FGL1 binding to LAG3 on macrophages leads to downregulation of TNFR1 expression and suppression of NF-κB signaling, promoting M2 macrophage polarization while inhibiting M1 activation and thereby enhancing liver repair.","method":"Acute liver injury mouse models, bone marrow-derived macrophage experiments, Western blot, cytokine measurement, flow cytometry","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments with defined pathway (LAG3→TNFR1→NF-κB), single lab","pmids":["41548433"],"is_preprint":false},{"year":2021,"finding":"An exome-wide association study identified an uncommon coding variant p.Trp256Leu in FGL1 that is associated with increased plasma D-dimer levels, supporting a role for FGL1 in hemostasis/fibrinolysis.","method":"Exome-wide association study, meta-analysis of 12 cohorts (n=19,306 for D-dimer), replication cohort","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — genetic association study without direct biochemical mechanistic experiment on the variant; replicated but no in vitro functional validation","pmids":["33876560"],"is_preprint":false},{"year":2025,"finding":"FGL1 produced by the liver is induced by IL-6 from CD4+ T cells in a primary Sjögren disease mouse model. FGL1 regulates naive and memory T cell homeostasis; Fgl1-deficient pSjD model mice showed earlier onset of autoimmune lesions compared to wild-type, indicating FGL1 suppresses T cell activation and delays autoimmunity onset.","method":"Fgl1-knockout mouse model of pSjD, immunologic analyses, genomic/bioinformatic analyses, cytokine measurement","journal":"Arthritis & rheumatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse with defined disease phenotype, IL-6-induced FGL1 axis identified, single lab","pmids":["40395191"],"is_preprint":false}],"current_model":"FGL1 is a liver-secreted fibrinogen-domain protein that functions as a major ligand for the immune checkpoint receptor LAG-3, inhibiting T cell and NK cell activation; its protein stability is regulated by ubiquitin ligases (FBXO38, TRIM21) and deubiquitinases (OTUD1, USP7), its transcription is controlled by STAT3, YY1, PRMT5-TCF12, SET1A-Yap, and KDM4A/KDM1A, and it additionally suppresses hepcidin synthesis by directly binding BMP6 to block BMP-SMAD signaling, while a post-translational glucosyl-galactosyl-hydroxylation at Lys65 mediated by LH3/GLT25D1 stabilizes the protein."},"narrative":{"mechanistic_narrative":"FGL1 (HFREP-1) is a liver-secreted fibrinogen-domain protein that lacks the platelet-binding, cross-linking, and thrombin-sensitive elements required to form fibrin clots [PMID:8390249], and which functions principally as a major functional ligand for the immune checkpoint receptor LAG-3, engaging LAG-3 through its fibrinogen domain to inhibit T cell activation and cytokine secretion [PMID:34526102, PMID:35111155]. In the liver microenvironment, hepatocyte-derived FGL1 acts via LAG-3 to suppress CD8+ T and NK cell function, and its genetic deletion or antibody blockade restores cytotoxic lymphocyte numbers and restrains liver metastasis [PMID:38973608]; the same axis constrains Treg suppressive activity and skews CD4+ T cell cytokine output [PMID:37916085], drives M2 macrophage polarization through TNFR1/NF-κB suppression to promote liver repair [PMID:41548433], and delays autoimmune onset by regulating T cell homeostasis [PMID:40395191]. FGL1 expression is induced by inflammatory IL-6 signaling in hepatocytes [PMID:37916085], and its transcription is controlled by a convergent set of regulators including STAT3—itself licensed by KDM4A-mediated H3K9me3 demethylation at the promoter [PMID:39085849] and by HDAC1-dependent JAK1 stability [PMID:39384195]—as well as YY1 [PMID:36268014], PRDM1 acting downstream of USP7 [PMID:38589688], PRMT5-methylated TCF12 [PMID:40041915], and SET1A-Yap in KRAS-driven tumors [PMID:39340215]. FGL1 protein abundance is set by opposing ubiquitin machinery, with the E3 ligases FBXO38 [PMID:37938970] and IRF1-induced TRIM21 [PMID:42020516] promoting proteasomal degradation while the deubiquitinase OTUD1, induced by macrophage NF-κB signaling, stabilizes the protein to drive metastasis [PMID:37872170]; an atypical glucosyl-galactosyl-hydroxylation at Lys65 catalyzed by LH3/GLT25D1 further stabilizes FGL1 [PMID:33984770]. Independently of immune signaling, FGL1 suppresses hepcidin synthesis by directly binding BMP6 to block BMP-SMAD signaling, linking it to iron homeostasis during anemia recovery [PMID:38232308]. An earlier body of work also defined FGL1 as a hepatocellular carcinoma growth suppressor whose tumor-restraining activity depends on an intact fibrinogen domain [PMID:14981537], a role that contrasts with its pro-tumor immune-evasive functions in other contexts.","teleology":[{"year":1993,"claim":"Established FGL1 as a liver- and HCC-expressed fibrinogen-family protein structurally incapable of clot formation, defining it as a secreted fibrinogen-domain protein rather than a coagulation factor.","evidence":"Subtractive cDNA cloning, sequence analysis, and Northern blot","pmids":["8390249"],"confidence":"Medium","gaps":["No receptor or binding partner identified","Functional role undefined at discovery"]},{"year":2004,"claim":"Showed that FGL1 restrains tumor growth, answering whether its liver/HCC expression reflects a functional role and assigning it a growth-suppressor activity dependent on intact protein sequence.","evidence":"Gene restoration, antisense knockdown, soft agar and nude mouse xenograft assays with missense mutants","pmids":["14981537"],"confidence":"High","gaps":["Mechanism of growth suppression not defined","Hard to reconcile with later pro-tumor immune-evasion roles"]},{"year":2016,"claim":"Demonstrated FGL1 can oligomerize with FGL2 in a distinct tissue context, indicating partner-dependent complex formation outside the liver-tumor axis.","evidence":"Proteomics, co-IP, and in situ localization in epididymis","pmids":["27732889"],"confidence":"Medium","gaps":["Functional consequence of FGL1-FGL2 binding to spermatozoa unresolved","Relevance to systemic FGL1 biology unclear"]},{"year":2021,"claim":"Identified LAG-3 as FGL1's major functional receptor and mapped the interaction to FGL1's fibrinogen domain and LAG-3 D1-D2, establishing FGL1 as an immune checkpoint ligand that inhibits T cell activation.","evidence":"Binding assays and T cell co-culture functional assays replicated across labs","pmids":["34526102","35111155"],"confidence":"High","gaps":["Structural basis of the interaction not detailed in timeline","Signaling events downstream of LAG-3 engagement not resolved here"]},{"year":2021,"claim":"Resolved how FGL1 protein levels are post-translationally maintained by identifying an atypical Lys65 glucosyl-galactosyl-hydroxylation that stabilizes the protein.","evidence":"LC-MS/MS, CRISPR knockout of LH3/GLT25D1, and site-directed mutagenesis","pmids":["33984770"],"confidence":"High","gaps":["How GGH alters folding/secretion mechanistically not defined","Whether the modification affects LAG-3 binding untested"]},{"year":2021,"claim":"Began defining FGL1 transcriptional control and a non-immune intracellular partner, showing YY1 drives FGL1 and FGL1 binds MYH9 to promote lung adenocarcinoma proliferation.","evidence":"ChIP, luciferase, Co-IP/MS, and proliferation assays in LUAD","pmids":["36268014"],"confidence":"Medium","gaps":["Mechanism by which intracellular FGL1-MYH9 promotes proliferation unclear","Relationship to secreted/checkpoint FGL1 pool not addressed"]},{"year":2023,"claim":"Established opposing ubiquitin-system control of FGL1 abundance, with FBXO38 ubiquitylating FGL1 for degradation and macrophage-induced OTUD1 deubiquitinating it, linking FGL1 stability to tumor immune evasion and metastasis.","evidence":"Co-IP, ubiquitination assays, ligase/DUB perturbation, and in vivo metastasis models","pmids":["37938970","37872170"],"confidence":"High","gaps":["Quantitative balance between ligase and DUB in normal physiology unknown","Degron on FGL1 not mapped"]},{"year":2023,"claim":"Extended the LAG-3 axis beyond conventional T cells, showing FGL1 limits Treg suppressive function and shifts CD4+ cytokine output, and that hepatocyte FGL1 is IL-6 inducible.","evidence":"Flow cytometry, ELISA, antibody blockade, and cytokine-stimulated hepatocytes","pmids":["37916085"],"confidence":"Medium","gaps":["Direct LAG-3 dependence of each cytokine effect not fully dissected","In vivo relevance to autoimmunity limited at this stage"]},{"year":2024,"claim":"Defined a hepcidin-suppressing, iron-regulatory function for FGL1 independent of immune signaling, via direct BMP6 binding and BMP-SMAD inhibition.","evidence":"Fgl1 knockout mice, in vitro BMP6 binding, and hepcidin/SMAD pathway readouts","pmids":["38232308"],"confidence":"High","gaps":["Structural basis of FGL1-BMP6 binding undefined","Crosstalk with FGL1's LAG-3 role not explored"]},{"year":2024,"claim":"Established the in vivo liver immunology of FGL1, showing hepatocyte FGL1 suppresses CD8+ T and NK cells through LAG-3 and that its blockade restrains metastasis in a cytotoxic-lymphocyte-dependent manner.","evidence":"Fgl1 knockout mice, anti-FGL1 mAb, LAG-3 inhibition assays, cell depletion and adoptive transfer","pmids":["38973608"],"confidence":"High","gaps":["Contribution of NK vs T cells to specific tumor types not separated","Therapeutic window of FGL1 blockade undefined"]},{"year":2024,"claim":"Assembled the upstream transcriptional and epigenetic network driving FGL1, converging on STAT3 (licensed by KDM4A demethylation and HDAC1/JAK1 stability), PRDM1 (USP7-stabilized), PRMT5-methylated TCF12, SET1A-Yap, and IRF1-TRIM21 degradation, explaining context-dependent FGL1 levels in tumor immune evasion.","evidence":"ChIP, luciferase, Co-IP, mass spectrometry, methylation/acetylation assays, and in vivo tumor models","pmids":["39085849","39384195","38589688","40041915","39340215","42020516"],"confidence":"High","gaps":["Hierarchy and tissue specificity among these regulators unresolved","Which inputs dominate in normal hepatocytes vs tumors unclear"]},{"year":2024,"claim":"Broadened FGL1's effector reach to innate immunity and additional cancers, showing LAG-3-dependent M2 macrophage polarization and FGL1 partners/effectors (CENPM, SOX5, IMPDH1) in diverse tumor contexts.","evidence":"Liver injury models, BMDM assays, Co-IP, rescue experiments in ACC/prostate/ESCC models","pmids":["41548433","39778025","39463328","38702629"],"confidence":"Medium","gaps":["Whether these partner interactions are direct and reciprocal varies by study","Integration with the canonical secreted/LAG-3 pool unclear"]},{"year":2025,"claim":"Linked FGL1 to systemic autoimmunity, showing IL-6-induced hepatic FGL1 regulates T cell homeostasis and delays Sjögren-like disease onset.","evidence":"Fgl1-knockout mouse model of primary Sjögren disease with immunologic profiling","pmids":["40395191"],"confidence":"Medium","gaps":["LAG-3 dependence in this model not formally proven","Translation to human disease untested"]},{"year":null,"claim":"How FGL1's roles as an HCC growth suppressor, a pro-tumor LAG-3 checkpoint ligand, and a hepcidin/iron regulator are reconciled within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural or signaling framework connecting tumor-suppressive and immune-evasive functions","Physiological vs pathological balance of the FGL1-LAG-3 axis undefined","Functional impact of the p.Trp256Leu hemostasis-associated variant not biochemically tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[5,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,5]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,16,19]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,16,21,22]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10]}],"complexes":["eFGL (FGL1-FGL2 disulfide-linked oligomer)"],"partners":["LAG3","BMP6","MYH9","FGL2","CENPM","SOX5","FBXO38","TRIM21"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q08830","full_name":"Fibrinogen-like protein 1","aliases":["HP-041","Hepassocin","HPS","Hepatocyte-derived fibrinogen-related protein 1","HFREP-1","Liver fibrinogen-related protein 1","LFIRE-1"],"length_aa":312,"mass_kda":36.4,"function":"Immune suppressive molecule that inhibits antigen-specific T-cell activation by acting as a ligand of LAG3 (PubMed:30580966, PubMed:35761082, PubMed:40101708). LAG3-binding initiates a signaling that inhibits the T-cell receptor (TCR) in the immunological synapse, preventing T-cell activation (PubMed:30580966). Binds LAG3 independently from MHC class II (MHC-II) (PubMed:30580966, PubMed:35761082). Secreted by, and promotes growth of, hepatocytes (PubMed:11470158, PubMed:19880967)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q08830/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FGL1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FGL1","total_profiled":1310},"omim":[{"mim_id":"605776","title":"FIBRINOGEN-LIKE 1; FGL1","url":"https://www.omim.org/entry/605776"},{"mim_id":"600288","title":"FORKHEAD BOX A2; FOXA2","url":"https://www.omim.org/entry/600288"},{"mim_id":"153337","title":"LYMPHOCYTE ACTIVATION GENE 3; LAG3","url":"https://www.omim.org/entry/153337"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":3863.2}],"url":"https://www.proteinatlas.org/search/FGL1"},"hgnc":{"alias_symbol":["HFREP-1","HPS"],"prev_symbol":[]},"alphafold":{"accession":"Q08830","domains":[{"cath_id":"3.90.215.10","chopping":"72-305","consensus_level":"high","plddt":96.2721,"start":72,"end":305},{"cath_id":"1.20.5","chopping":"2-66","consensus_level":"medium","plddt":79.1526,"start":2,"end":66}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08830","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q08830-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q08830-F1-predicted_aligned_error_v6.png","plddt_mean":90.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FGL1","jax_strain_url":"https://www.jax.org/strain/search?query=FGL1"},"sequence":{"accession":"Q08830","fasta_url":"https://rest.uniprot.org/uniprotkb/Q08830.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q08830/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08830"}},"corpus_meta":[{"pmid":"35111155","id":"PMC_35111155","title":"Immune 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was identified as a novel fibrinogen-related protein specifically expressed in liver and hepatocellular carcinoma. The deduced protein sequence contained a hydrophobic leader peptide and showed marked homology with beta- and gamma-subunits of fibrinogen, but lacked a platelet-binding site, cross-linking region, and thrombin-sensitive site, indicating it cannot form fibrin clots.\",\n      \"method\": \"Subtractive/differential cDNA cloning, sequence analysis, Northern blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — original cloning paper with sequence analysis and tissue expression, single lab but foundational characterization\",\n      \"pmids\": [\"8390249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"LFIRE-1/HFREP-1 (FGL1) encodes a growth suppressor in hepatocellular carcinoma. Restoration of wild-type FGL1 expression in HCC cells inhibited anchorage-dependent and -independent growth in vitro and suppressed tumorigenicity in nude mice, whereas FGL1 missense mutations failed to do so. Antisense-mediated reduction of FGL1 enhanced cancer cell proliferation and colony formation.\",\n      \"method\": \"Exogenous gene restoration, antisense knockdown, colony formation assay, soft agar assay, nude mouse xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (gain-of-function, loss-of-function, in vivo), mutation analysis showing domain dependence, replicated across assays\",\n      \"pmids\": [\"14981537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FGL1 forms disulfide-linked oligomers with FGL2 in the epididymis. These oligomers (eFGL) specifically bind nonviable spermatozoa in the cauda epididymidis. Co-immunoprecipitation using anti-FGL2 antibody demonstrated that both FGL1 and FGL2 are present in the soluble eFGL complex. FGL1 is expressed in principal cells of the proximal cauda epididymidis.\",\n      \"method\": \"Proteomics (LC-MS), PCR-based cloning, co-immunoprecipitation, immunocytochemistry, Northern blot, in situ hybridization\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (proteomics, co-IP, localization), single lab\",\n      \"pmids\": [\"27732889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FGL1 confers acquired resistance to gefitinib in NSCLC by regulating the PARP1/caspase-3 apoptosis pathway. FGL1 knockdown suppressed cell viability, reduced gefitinib IC50, and enhanced apoptosis in PC9/GR cells; mechanistically, FGL1 inhibition reduced PARP1 and caspase-3 expression upon gefitinib treatment.\",\n      \"method\": \"siRNA knockdown, CCK-8 assay, colony formation, flow cytometry, Western blot, mouse xenograft, immunohistochemistry\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo knockdown with pathway readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32778129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Oxysophocarpine sensitized LAG-3 immunotherapy against HCC by decreasing FGL1 expression through downregulation of IL-6-mediated JAK2/STAT3 signaling. This effect was specific to the LAG-3 pathway, as oxysophocarpine had little effect on CD8+ T cell cytotoxicity with PD-1, Tim-3, or TIGIT blockade.\",\n      \"method\": \"In vitro cell assays, in vivo subcutaneous tumor model, Western blot, flow cytometry\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments with pathway specificity controls, single lab\",\n      \"pmids\": [\"32810392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FGL1 is a major functional ligand of the immune checkpoint receptor LAG-3 (lymphocyte activation gene 3). FGL1 binding to LAG-3 on T cells inhibits T cell activation and cytokine secretion. The D1-D2 domains of LAG-3 and the fibrinogen domain (FD) of FGL1 mediate this interaction.\",\n      \"method\": \"Binding assays, functional T cell co-culture assays (referenced across multiple papers as established finding)\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — interaction and functional consequence independently replicated across multiple labs and multiple experimental systems\",\n      \"pmids\": [\"34526102\", \"35111155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Glucosyl-galactosyl-hydroxylation (GGH) post-translational modification occurs at Lys65 of FGL1, despite FGL1 lacking a collagen-like domain. This modification is carried out by the glycosyltransferases LH3 and GLT25D1. Knockout of LH3 or GLT25D1 significantly inhibited glycosylation, and deficiency of GGH (via point mutation or glycosyltransferase knockout) reduced FGL1 protein levels.\",\n      \"method\": \"LC-MS/MS analysis, LH3/GLT25D1-knockout cell lines (CRISPR), site-directed mutagenesis, Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro mass spectrometry identification of PTM site, confirmed by mutagenesis and knockout cell lines, multiple orthogonal approaches in single rigorous study\",\n      \"pmids\": [\"33984770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FGL1 promotes proliferation of lung adenocarcinoma (LUAD) cells in vitro and in vivo, and is transcriptionally regulated by the transcription factor YY1. FGL1 directly binds MYH9 (identified by immunoprecipitation and mass spectrometry) to promote LUAD cell proliferation.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, chromatin immunoprecipitation, dual luciferase reporter assay, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS for binding partner, ChIP and luciferase for transcription factor, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36268014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO38, an E3 ubiquitin ligase, directly interacts with FGL1 and ubiquitylates it to promote its proteasomal degradation. Depletion of FBXO38 markedly augments FGL1 protein abundance, suppressing CD8+ T cell infiltration and enhancing tumor immune evasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, FBXO38 knockout/knockdown, flow cytometry, Western blot\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct ubiquitination assay with E3 ligase identification, Co-IP for interaction, functional cellular readout, multiple methods in single rigorous study\",\n      \"pmids\": [\"37938970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Tumor-associated macrophages (TAMs) activate NF-κB by secreting TNFα/IL-1β in the liver microenvironment, which transcriptionally upregulates OTUD1 (a deubiquitinase). OTUD1 then enhances FGL1 protein stability via deubiquitination, promoting metastatic tumor progression.\",\n      \"method\": \"Mechanistic experiments in intraportal injection model, Western blot, ubiquitination assay, NF-κB reporter assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — deubiquitination mechanism established with in vivo model, multiple orthogonal methods, published in high-impact journal\",\n      \"pmids\": [\"37872170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FGL1 is a potent suppressor of hepcidin synthesis. FGL1 exerts this activity by directly binding to BMP6, thereby inhibiting the canonical BMP-SMAD signaling cascade that controls hepcidin transcription. Deletion of Fgl1 in mice results in higher hepcidin levels at baseline and after bleeding, and FGL1 is induced in the liver in response to hypoxia during anemia recovery.\",\n      \"method\": \"Fgl1 knockout mice, in vitro binding assays (BMP6 binding), hepcidin quantification in vitro and in vivo, BMP-SMAD pathway analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding demonstrated in vitro, genetic KO in vivo with pathway readout, published in peer-reviewed high-impact journal with complementary preprint data\",\n      \"pmids\": [\"38232308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC1 deacetylates JAK1; SAHA (HDACi) inhibits HDAC1, increasing acetylation of JAK1 at lysine 1109, promoting its proteasomal degradation and reducing STAT3-driven FGL1 transcription. This mechanism underlies SAHA-mediated suppression of FGL1 and enhancement of CD8+ T cell antitumor activity in lung adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, mass spectrometry, RNA sequencing, Western blot, ELISA, in vitro co-culture, in vivo tumor models\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — acetylation site identified by mass spectrometry, ChIP for transcriptional regulation, in vitro and in vivo functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"39384195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP7 deubiquitinates the transcription factor PRDM1, stabilizing it. PRDM1 then transcriptionally activates FGL1 expression in liver cancer cells, attenuating CD8+ T cell activity. A positive feedback loop exists in which PRDM1 also transcriptionally stimulates USP7.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, chromatin immunoprecipitation, in vivo xenograft, flow cytometry\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and deubiquitination assay demonstrate mechanism, ChIP for transcriptional regulation, functional validation in vivo, single lab\",\n      \"pmids\": [\"38589688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT5 catalyzes symmetric dimethylation of transcription factor TCF12 at arginine 554 (R554), promoting TCF12 binding to the FGL1 promoter and transcriptionally activating FGL1 in liver cancer cells. Methylation-deficient TCF12-R554 mutants fail to activate FGL1 transcription, and PRMT5 inhibition reduces FGL1 and enhances CD8+ T cell antitumor immunity.\",\n      \"method\": \"In vitro methylation assay, site-directed mutagenesis, chromatin immunoprecipitation, luciferase reporter assay, in vivo tumor models, flow cytometry\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — enzymatic methylation at specific residue identified, mutagenesis validation, ChIP and luciferase for transcriptional mechanism, in vivo functional readout\",\n      \"pmids\": [\"40041915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM4A interacts with STAT3 and facilitates removal of methyl groups from H3K9me3 at the FGL1 promoter, enhancing STAT3-mediated transcription of FGL1 in NSCLC cells. STAT3 acts as a direct transcription factor for FGL1 by binding its promoter.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, FGL1 promoter activity assay, Western blot, cell proliferation/migration assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for KDM4A-STAT3 interaction, ChIP for promoter occupancy, functional validation, single lab\",\n      \"pmids\": [\"39085849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KRAS activates ERK1/2, which phosphorylates SET1A histone methyltransferase, increasing its stability and nuclear localization. SET1A-mediated methylation of Yap promotes its nuclear sequestration, driving Yap-induced transcription of FGL1 to promote immune evasion in KRAS-driven lung adenocarcinoma.\",\n      \"method\": \"Chromatin immunoprecipitation, dual luciferase reporter assay, lentiviral overexpression/silencing, flow cytometry, immunofluorescence, in vivo mouse models\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase for transcriptional mechanism, multiple pathway components validated, single lab\",\n      \"pmids\": [\"39340215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hepatocyte-derived FGL1 directly inhibits hepatic CD8+ T and NK cell functions via the receptor LAG-3 in the liver microenvironment. Fgl1-deficient mice showed increased hepatic CD8+ T and NK cell numbers and functions, and anti-FGL1 mAb blockade restrained liver metastasis. The antitumor efficacy of FGL1 blockade was dependent on cytotoxic T lymphocytes and NK cells as demonstrated by cell-deficient models and cell transfer in vivo.\",\n      \"method\": \"Fgl1 knockout mice, anti-FGL1 mAb treatment, in vitro inhibition assays with LAG-3, cell depletion models, adoptive cell transfer, flow cytometry\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and antibody blockade converge on same phenotype, in vitro direct inhibition via LAG-3 confirmed, cell depletion experiments establish mechanism, multiple orthogonal approaches\",\n      \"pmids\": [\"38973608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM21 (an E3 ubiquitin ligase) targets FGL1 for proteasomal degradation, and this process is transcriptionally regulated by IRF1 (which activates TRIM21 transcription). Artemisinin upregulates the IRF1-TRIM21 axis, promoting FGL1 degradation and enhancing antitumor CTL activity.\",\n      \"method\": \"Western blot, ubiquitination assay, luciferase reporter assay, chromatin immunoprecipitation, in vivo tumor models, flow cytometry\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay demonstrates E3 ligase mechanism, ChIP and luciferase for transcriptional regulation, functional in vivo validation, single lab\",\n      \"pmids\": [\"42020516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CENPM physically interacts with FGL1 in adrenocortical carcinoma cells, as demonstrated by co-immunoprecipitation and DIA quantitative proteomics. Overexpression of FGL1 rescued migration and invasion of CENPM knockdown ACC cells, placing FGL1 downstream of CENPM in ACC metastasis.\",\n      \"method\": \"DIA quantitative proteomics, co-immunoprecipitation, immunofluorescence, Western blot, migration/invasion assays, xenograft model\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with proteomics for binding partner, rescue experiments for epistasis, single lab\",\n      \"pmids\": [\"39778025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FGL1 secreted from cancer-associated fibroblast (CAF)-derived exosomes interacts with SOX5 in prostate cancer cells and negatively regulates SOX5 expression, promoting PC cell viability, migration, and invasion via the FGL1/SOX5 axis.\",\n      \"method\": \"Co-immunoprecipitation, FISH, CCK-8, Transwell assay, rescue experiments, in vivo tumor model\",\n      \"journal\": \"Histology and histopathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for interaction, single lab, limited functional validation\",\n      \"pmids\": [\"39463328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Radiation-induced upregulation of FGL1 in esophageal squamous cell carcinoma is mediated by the transcription factor FOXO4. FGL1 promotes ESCC metastasis through upregulation of IMPDH1; IMPDH1 knockdown reversed the pro-invasive effects of FGL1.\",\n      \"method\": \"qRT-PCR, Western blot, immunofluorescence, Transwell assay, wound healing, RNA sequencing, nude mouse models, rescue experiments\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiments establish epistasis (FGL1→IMPDH1), multiple assays, single lab\",\n      \"pmids\": [\"38702629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FGL1 binding to LAG3 inhibits Treg cell proliferation and impairs the suppressive activity of Treg cells by limiting IL-10 secretion, and promotes pathogenic IL-17a and IL-21 production by CD4+ T cells. FGL1 expression in hepatocytes is induced by the inflammatory cytokine IL-6 signaling.\",\n      \"method\": \"Flow cytometry, ELISA, cell culture assays with functional antibody blockade, hepatocyte stimulation with cytokines\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blockade experiment defines LAG3-mediated Treg suppression mechanism, IL-6-induced FGL1 in hepatocytes confirmed in vitro, single lab\",\n      \"pmids\": [\"37916085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FGL1 binding to LAG3 on macrophages leads to downregulation of TNFR1 expression and suppression of NF-κB signaling, promoting M2 macrophage polarization while inhibiting M1 activation and thereby enhancing liver repair.\",\n      \"method\": \"Acute liver injury mouse models, bone marrow-derived macrophage experiments, Western blot, cytokine measurement, flow cytometry\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments with defined pathway (LAG3→TNFR1→NF-κB), single lab\",\n      \"pmids\": [\"41548433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"An exome-wide association study identified an uncommon coding variant p.Trp256Leu in FGL1 that is associated with increased plasma D-dimer levels, supporting a role for FGL1 in hemostasis/fibrinolysis.\",\n      \"method\": \"Exome-wide association study, meta-analysis of 12 cohorts (n=19,306 for D-dimer), replication cohort\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — genetic association study without direct biochemical mechanistic experiment on the variant; replicated but no in vitro functional validation\",\n      \"pmids\": [\"33876560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FGL1 produced by the liver is induced by IL-6 from CD4+ T cells in a primary Sjögren disease mouse model. FGL1 regulates naive and memory T cell homeostasis; Fgl1-deficient pSjD model mice showed earlier onset of autoimmune lesions compared to wild-type, indicating FGL1 suppresses T cell activation and delays autoimmunity onset.\",\n      \"method\": \"Fgl1-knockout mouse model of pSjD, immunologic analyses, genomic/bioinformatic analyses, cytokine measurement\",\n      \"journal\": \"Arthritis & rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse with defined disease phenotype, IL-6-induced FGL1 axis identified, single lab\",\n      \"pmids\": [\"40395191\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FGL1 is a liver-secreted fibrinogen-domain protein that functions as a major ligand for the immune checkpoint receptor LAG-3, inhibiting T cell and NK cell activation; its protein stability is regulated by ubiquitin ligases (FBXO38, TRIM21) and deubiquitinases (OTUD1, USP7), its transcription is controlled by STAT3, YY1, PRMT5-TCF12, SET1A-Yap, and KDM4A/KDM1A, and it additionally suppresses hepcidin synthesis by directly binding BMP6 to block BMP-SMAD signaling, while a post-translational glucosyl-galactosyl-hydroxylation at Lys65 mediated by LH3/GLT25D1 stabilizes the protein.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FGL1 (HFREP-1) is a liver-secreted fibrinogen-domain protein that lacks the platelet-binding, cross-linking, and thrombin-sensitive elements required to form fibrin clots [#0], and which functions principally as a major functional ligand for the immune checkpoint receptor LAG-3, engaging LAG-3 through its fibrinogen domain to inhibit T cell activation and cytokine secretion [#5]. In the liver microenvironment, hepatocyte-derived FGL1 acts via LAG-3 to suppress CD8+ T and NK cell function, and its genetic deletion or antibody blockade restores cytotoxic lymphocyte numbers and restrains liver metastasis [#16]; the same axis constrains Treg suppressive activity and skews CD4+ T cell cytokine output [#21], drives M2 macrophage polarization through TNFR1/NF-κB suppression to promote liver repair [#22], and delays autoimmune onset by regulating T cell homeostasis [#24]. FGL1 expression is induced by inflammatory IL-6 signaling in hepatocytes [#21], and its transcription is controlled by a convergent set of regulators including STAT3—itself licensed by KDM4A-mediated H3K9me3 demethylation at the promoter [#14] and by HDAC1-dependent JAK1 stability [#11]—as well as YY1 [#7], PRDM1 acting downstream of USP7 [#12], PRMT5-methylated TCF12 [#13], and SET1A-Yap in KRAS-driven tumors [#15]. FGL1 protein abundance is set by opposing ubiquitin machinery, with the E3 ligases FBXO38 [#8] and IRF1-induced TRIM21 [#17] promoting proteasomal degradation while the deubiquitinase OTUD1, induced by macrophage NF-κB signaling, stabilizes the protein to drive metastasis [#9]; an atypical glucosyl-galactosyl-hydroxylation at Lys65 catalyzed by LH3/GLT25D1 further stabilizes FGL1 [#6]. Independently of immune signaling, FGL1 suppresses hepcidin synthesis by directly binding BMP6 to block BMP-SMAD signaling, linking it to iron homeostasis during anemia recovery [#10]. An earlier body of work also defined FGL1 as a hepatocellular carcinoma growth suppressor whose tumor-restraining activity depends on an intact fibrinogen domain [#1], a role that contrasts with its pro-tumor immune-evasive functions in other contexts.\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established FGL1 as a liver- and HCC-expressed fibrinogen-family protein structurally incapable of clot formation, defining it as a secreted fibrinogen-domain protein rather than a coagulation factor.\",\n      \"evidence\": \"Subtractive cDNA cloning, sequence analysis, and Northern blot\",\n      \"pmids\": [\"8390249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor or binding partner identified\", \"Functional role undefined at discovery\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed that FGL1 restrains tumor growth, answering whether its liver/HCC expression reflects a functional role and assigning it a growth-suppressor activity dependent on intact protein sequence.\",\n      \"evidence\": \"Gene restoration, antisense knockdown, soft agar and nude mouse xenograft assays with missense mutants\",\n      \"pmids\": [\"14981537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of growth suppression not defined\", \"Hard to reconcile with later pro-tumor immune-evasion roles\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated FGL1 can oligomerize with FGL2 in a distinct tissue context, indicating partner-dependent complex formation outside the liver-tumor axis.\",\n      \"evidence\": \"Proteomics, co-IP, and in situ localization in epididymis\",\n      \"pmids\": [\"27732889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of FGL1-FGL2 binding to spermatozoa unresolved\", \"Relevance to systemic FGL1 biology unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified LAG-3 as FGL1's major functional receptor and mapped the interaction to FGL1's fibrinogen domain and LAG-3 D1-D2, establishing FGL1 as an immune checkpoint ligand that inhibits T cell activation.\",\n      \"evidence\": \"Binding assays and T cell co-culture functional assays replicated across labs\",\n      \"pmids\": [\"34526102\", \"35111155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the interaction not detailed in timeline\", \"Signaling events downstream of LAG-3 engagement not resolved here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved how FGL1 protein levels are post-translationally maintained by identifying an atypical Lys65 glucosyl-galactosyl-hydroxylation that stabilizes the protein.\",\n      \"evidence\": \"LC-MS/MS, CRISPR knockout of LH3/GLT25D1, and site-directed mutagenesis\",\n      \"pmids\": [\"33984770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GGH alters folding/secretion mechanistically not defined\", \"Whether the modification affects LAG-3 binding untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Began defining FGL1 transcriptional control and a non-immune intracellular partner, showing YY1 drives FGL1 and FGL1 binds MYH9 to promote lung adenocarcinoma proliferation.\",\n      \"evidence\": \"ChIP, luciferase, Co-IP/MS, and proliferation assays in LUAD\",\n      \"pmids\": [\"36268014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which intracellular FGL1-MYH9 promotes proliferation unclear\", \"Relationship to secreted/checkpoint FGL1 pool not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established opposing ubiquitin-system control of FGL1 abundance, with FBXO38 ubiquitylating FGL1 for degradation and macrophage-induced OTUD1 deubiquitinating it, linking FGL1 stability to tumor immune evasion and metastasis.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, ligase/DUB perturbation, and in vivo metastasis models\",\n      \"pmids\": [\"37938970\", \"37872170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative balance between ligase and DUB in normal physiology unknown\", \"Degron on FGL1 not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the LAG-3 axis beyond conventional T cells, showing FGL1 limits Treg suppressive function and shifts CD4+ cytokine output, and that hepatocyte FGL1 is IL-6 inducible.\",\n      \"evidence\": \"Flow cytometry, ELISA, antibody blockade, and cytokine-stimulated hepatocytes\",\n      \"pmids\": [\"37916085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LAG-3 dependence of each cytokine effect not fully dissected\", \"In vivo relevance to autoimmunity limited at this stage\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a hepcidin-suppressing, iron-regulatory function for FGL1 independent of immune signaling, via direct BMP6 binding and BMP-SMAD inhibition.\",\n      \"evidence\": \"Fgl1 knockout mice, in vitro BMP6 binding, and hepcidin/SMAD pathway readouts\",\n      \"pmids\": [\"38232308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FGL1-BMP6 binding undefined\", \"Crosstalk with FGL1's LAG-3 role not explored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established the in vivo liver immunology of FGL1, showing hepatocyte FGL1 suppresses CD8+ T and NK cells through LAG-3 and that its blockade restrains metastasis in a cytotoxic-lymphocyte-dependent manner.\",\n      \"evidence\": \"Fgl1 knockout mice, anti-FGL1 mAb, LAG-3 inhibition assays, cell depletion and adoptive transfer\",\n      \"pmids\": [\"38973608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of NK vs T cells to specific tumor types not separated\", \"Therapeutic window of FGL1 blockade undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Assembled the upstream transcriptional and epigenetic network driving FGL1, converging on STAT3 (licensed by KDM4A demethylation and HDAC1/JAK1 stability), PRDM1 (USP7-stabilized), PRMT5-methylated TCF12, SET1A-Yap, and IRF1-TRIM21 degradation, explaining context-dependent FGL1 levels in tumor immune evasion.\",\n      \"evidence\": \"ChIP, luciferase, Co-IP, mass spectrometry, methylation/acetylation assays, and in vivo tumor models\",\n      \"pmids\": [\"39085849\", \"39384195\", \"38589688\", \"40041915\", \"39340215\", \"42020516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy and tissue specificity among these regulators unresolved\", \"Which inputs dominate in normal hepatocytes vs tumors unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Broadened FGL1's effector reach to innate immunity and additional cancers, showing LAG-3-dependent M2 macrophage polarization and FGL1 partners/effectors (CENPM, SOX5, IMPDH1) in diverse tumor contexts.\",\n      \"evidence\": \"Liver injury models, BMDM assays, Co-IP, rescue experiments in ACC/prostate/ESCC models\",\n      \"pmids\": [\"41548433\", \"39778025\", \"39463328\", \"38702629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these partner interactions are direct and reciprocal varies by study\", \"Integration with the canonical secreted/LAG-3 pool unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked FGL1 to systemic autoimmunity, showing IL-6-induced hepatic FGL1 regulates T cell homeostasis and delays Sjögren-like disease onset.\",\n      \"evidence\": \"Fgl1-knockout mouse model of primary Sjögren disease with immunologic profiling\",\n      \"pmids\": [\"40395191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LAG-3 dependence in this model not formally proven\", \"Translation to human disease untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FGL1's roles as an HCC growth suppressor, a pro-tumor LAG-3 checkpoint ligand, and a hepcidin/iron regulator are reconciled within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural or signaling framework connecting tumor-suppressive and immune-evasive functions\", \"Physiological vs pathological balance of the FGL1-LAG-3 axis undefined\", \"Functional impact of the p.Trp256Leu hemostasis-associated variant not biochemically tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [5, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 16, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 16, 21, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\"eFGL (FGL1-FGL2 disulfide-linked oligomer)\"],\n    \"partners\": [\"LAG3\", \"BMP6\", \"MYH9\", \"FGL2\", \"CENPM\", \"SOX5\", \"FBXO38\", \"TRIM21\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}