{"gene":"LGALS1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2026,"finding":"DUSP22 binds to LGALS1 and dephosphorylates it at Ser8 and Thr58 residues, leading to LGALS1 protein degradation and subsequent alleviation of LGALS1-mediated immunosuppression; this was confirmed by mass spectrometry, co-immunoprecipitation, and phosphomimetic mutant experiments.","method":"Mass spectrometry, co-immunoprecipitation, phosphomimetic mutagenesis, flow cytometry, mouse models","journal":"Journal for immunotherapy of cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal Co-IP, phosphomimetic mutagenesis confirming specific sites, in vivo validation, multiple orthogonal methods in one study","pmids":["41611244"],"is_preprint":false},{"year":2026,"finding":"Tumor cell-secreted LGALS1 binds with high affinity to CD276 (B7-H3) on endothelial cells, with the interaction mediated by N-linked glycosylation at the N433 site within the D4 domain of CD276; this interaction activates MAP4-dependent PI3K/AKT signaling to promote angiogenesis and bladder cancer progression.","method":"Human proteome microarray, co-immunoprecipitation, glycosylation site mutagenesis, subcutaneous and orthotopic mouse models, Cd276−/− and Lgals1−/− mouse models","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — proteome microarray binding identification, mutagenesis of interaction site, validated in knockout mouse models, multiple orthogonal methods","pmids":["42230983"],"is_preprint":false},{"year":2018,"finding":"LGALS1 knockdown in highly invasive oral cancer cells inactivates p38 MAPK phosphorylation, downregulates MMP-9, and inhibits epithelial-mesenchymal transition (EMT), establishing LGALS1 as an upstream regulator of the p38 MAPK/MMP-9/EMT axis in oral cancer metastasis.","method":"siRNA knockdown, in vitro migration/invasion assays, in vivo mouse metastasis model, western blot for p38 MAPK phosphorylation and MMP-9","journal":"Therapeutic advances in medical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype and pathway placement, in vitro and in vivo, single lab","pmids":["30159048"],"is_preprint":false},{"year":2023,"finding":"LGALS1+ fibroblasts promote proliferation and migration of intrahepatic cholangiocarcinoma cells by upregulating CCR2, ADAM15, and β-integrin expression; silencing LGALS1 in cancer-associated fibroblasts suppressed tumor cell migration and invasion in vitro and tumor formation in vivo.","method":"Single-cell RNA sequencing, siRNA knockdown in CAFs, in vitro co-culture migration/invasion assays, in vivo tumor formation model","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — scRNA-seq identification, functional KD with defined phenotype and downstream targets, in vivo validation, single lab","pmids":["38862197"],"is_preprint":false},{"year":2026,"finding":"CAF-derived miR-181b-5p targets SEC24C in pancreatic cancer cells to inhibit STING phosphorylation, which blocks YY1 nuclear translocation and de-represses LGALS1 transcription; upregulated LGALS1 is then secreted via SUSD2 assistance to suppress CD8+ T cell function and induce apoptosis.","method":"In vitro T cell suppression assays, in vivo mouse models, pathway inhibition experiments, mechanistic reporter and expression assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pathway placed by multiple mechanistic steps with in vitro and in vivo validation, single lab","pmids":["41713839"],"is_preprint":false},{"year":2020,"finding":"LGALS1 knockdown in AML cell lines sensitized them to BCL2 inhibitor ABT-737, and in vivo shRNA-mediated LGALS1 suppression in a murine OCI-AML3 xenograft model significantly prolonged survival, demonstrating a pro-survival function of LGALS1 in AML.","method":"shRNA knockdown, murine xenograft model, RNASeq gene expression profiling","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean in vivo KD with survival phenotype, RNASeq pathway profiling, single lab","pmids":["32590026"],"is_preprint":false},{"year":2019,"finding":"Knockdown of LGALS1 in glioblastoma remodels the immunosuppressive microenvironment by downregulating M2 macrophages and myeloid-derived suppressor cells (MDSCs) and inhibiting immunosuppressive cytokines, placing LGALS1 as a regulator of myeloid cell polarization in the tumor microenvironment.","method":"LGALS1 knockdown in vitro and in vivo, flow cytometry for immune cell populations, cytokine measurement","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vitro and in vivo KD with defined immunological phenotypes, single lab","pmids":["30613962"],"is_preprint":false},{"year":2024,"finding":"LGALS1 overexpression in kidney tubular TCMK-1 cells increased fibrosis markers and upregulated PI3K and AKT phosphorylation, establishing LGALS1 as an activator of the PI3K/AKT signaling pathway in renal fibrosis.","method":"LGALS1 overexpression in TCMK-1 cells, Western blot for PI3K/AKT phosphorylation, TGF-β-induced fibrosis model","journal":"Renal failure","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment with western blot, single lab, no mutagenesis or reconstitution","pmids":["38967135"],"is_preprint":false},{"year":2024,"finding":"LGALS1 repression in AML cells inhibited proliferation, enhanced apoptosis, decreased lipid accumulation, and curbed AML progression in vivo; LGALS1 repression also reduced CD8+ T and NK cell suppression in vivo, linking LGALS1 to fatty acid metabolism and immune evasion in leukemia stem cells.","method":"LGALS1 knockdown in vitro and in vivo, flow cytometry for immune cells, lipid accumulation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vitro and in vivo KD with multiple phenotypic readouts, single lab","pmids":["38965225"],"is_preprint":false},{"year":2022,"finding":"LGALS1 silencing in NSCLC A549 cells altered alternative splicing of BCAP29, CSNKIE, and MDFIC and regulated expression of ELMO1, KCNJ2, and HSPA6, with LGALS1 overexpression rescuing these changes, identifying LGALS1 as an RNA-binding protein regulating alternative splicing in NSCLC.","method":"siRNA knockdown, RNA sequencing, RT-qPCR, LGALS1 overexpression rescue","journal":"Advances in clinical and experimental medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RNA-seq with partial RT-qPCR validation, no direct RBP binding assay confirming mechanism","pmids":["37341175"],"is_preprint":false},{"year":2022,"finding":"miR-22-3p directly binds to LGALS1 mRNA (confirmed by dual luciferase assay); overexpression of miR-22-3p in melanoma cells decreased LGALS1 expression, reduced VIM and SNAI2, increased CDH1, and inhibited EMT, establishing LGALS1 as a target of miR-22-3p-mediated EMT regulation in melanoma.","method":"Dual luciferase reporter assay, miR-22-3p overexpression, western blot for EMT markers, cell viability and apoptosis assays","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual luciferase confirming direct binding, functional overexpression with downstream marker validation, single lab","pmids":["36224027"],"is_preprint":false},{"year":2026,"finding":"In glioblastoma, TGFBR2 expression in mesenchymal glioma stem cells drives a 6-gene immunosuppressive Treg-like signature that includes LGALS1 (galectin-1), and TGFBR2 inhibition reversed this signature and restored CD4+ and CD8+ T cell function.","method":"Transgenic TGFBR2 expression, shRNA-based TGFBR2 inhibition, single-cell sequencing, T cell viability assays","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — LGALS1 identified as part of a multi-gene signature downstream of TGFBR2, not specifically validated for LGALS1 alone; preprint","pmids":[],"is_preprint":true}],"current_model":"LGALS1 (Galectin-1) is a secreted lectin and intracellular signaling protein that promotes tumor immune evasion by suppressing CD8+ T cells and promoting M2 macrophage/MDSC polarization; its stability is regulated by DUSP22-mediated dephosphorylation at Ser8/Thr58 (leading to degradation), and it drives pro-tumorigenic signaling through binding CD276 on endothelial cells to activate MAP4/PI3K/AKT-dependent angiogenesis, acting downstream of p38 MAPK/MMP-9/EMT pathways in metastasis, and functioning as an RNA-binding protein that regulates alternative splicing in cancer cells."},"narrative":{"mechanistic_narrative":"LGALS1 (Galectin-1) is a secreted lectin that functions as a central driver of tumor immune evasion and pro-tumorigenic signaling across multiple cancers [PMID:42230983, PMID:30613962]. Tumor- and fibroblast-derived LGALS1 reshapes the immune microenvironment, suppressing CD8+ T cell and NK cell function and reducing M2 macrophage and myeloid-derived suppressor cell populations upon its loss [PMID:30613962, PMID:38965225]. Mechanistically, tumor-secreted LGALS1 binds with high affinity to CD276 (B7-H3) on endothelial cells through N-linked glycosylation at N433 in the CD276 D4 domain, activating MAP4-dependent PI3K/AKT signaling to promote angiogenesis and bladder cancer progression [PMID:42230983]. In addition, LGALS1 acts as an upstream activator of a p38 MAPK/MMP-9 axis that drives epithelial-mesenchymal transition and metastasis [PMID:30159048], and in cancer-associated fibroblasts it promotes tumor cell proliferation and migration by upregulating CCR2, ADAM15, and β-integrin [PMID:38862197]. LGALS1 protein abundance is controlled post-translationally: DUSP22 binds and dephosphorylates LGALS1 at Ser8 and Thr58, triggering its degradation and relieving LGALS1-mediated immunosuppression [PMID:41611244]. Its expression is further regulated through miRNA targeting, including direct binding by miR-22-3p [PMID:36224027], and a CAF-derived miR-181b-5p/SEC24C/STING/YY1 axis that de-represses LGALS1 transcription [PMID:41713839]. LGALS1 also confers a pro-survival, lipid-metabolism-linked phenotype in acute myeloid leukemia [PMID:32590026, PMID:38965225].","teleology":[{"year":2018,"claim":"Established LGALS1 as a functional upstream driver of metastasis rather than a passive marker, by placing it at the head of a defined signaling axis.","evidence":"siRNA knockdown in invasive oral cancer cells with migration/invasion assays, an in vivo metastasis model, and Western blot for p38 MAPK and MMP-9","pmids":["30159048"],"confidence":"Medium","gaps":["Does not show direct molecular binding linking LGALS1 to p38 activation","Mechanism of how a secreted lectin engages intracellular p38 signaling not resolved"]},{"year":2019,"claim":"Showed LGALS1 controls the myeloid arm of the immunosuppressive tumor microenvironment, defining it as a regulator of M2 macrophage and MDSC polarization.","evidence":"LGALS1 knockdown in vitro and in vivo in glioblastoma with flow cytometry for immune populations and cytokine measurement","pmids":["30613962"],"confidence":"Medium","gaps":["Receptor mediating myeloid polarization not identified","Cannot distinguish secreted vs intracellular contributions"]},{"year":2020,"claim":"Demonstrated a cell-autonomous pro-survival role for LGALS1 in leukemia, linking it to apoptotic threshold and therapeutic sensitivity.","evidence":"shRNA knockdown in AML cell lines with ABT-737 sensitization and survival readout in a murine OCI-AML3 xenograft, plus RNASeq","pmids":["32590026"],"confidence":"Medium","gaps":["Molecular link to BCL2-family apoptotic machinery not defined","Single lab"]},{"year":2022,"claim":"Identified upstream transcriptional control of LGALS1 by miR-22-3p, connecting its expression level to EMT regulation in melanoma.","evidence":"Dual luciferase reporter assay confirming direct mRNA binding, miR-22-3p overexpression with EMT marker Western blots","pmids":["36224027"],"confidence":"Medium","gaps":["Does not establish LGALS1's own downstream effector mechanism in melanoma","In vivo relevance not tested"]},{"year":2022,"claim":"Proposed an intracellular, non-lectin function for LGALS1 as an RNA-binding protein controlling alternative splicing.","evidence":"siRNA knockdown plus RNA-seq with RT-qPCR and overexpression rescue in NSCLC A549 cells","pmids":["37341175"],"confidence":"Low","gaps":["No direct RBP binding assay (CLIP/EMSA) confirming physical RNA interaction","Splicing targets validated only at expression level"]},{"year":2023,"claim":"Defined a stromal source of LGALS1 in cancer-associated fibroblasts and its downstream effectors driving tumor cell invasion.","evidence":"scRNA-seq identification with siRNA knockdown in CAFs, co-culture invasion assays, and in vivo tumor formation in cholangiocarcinoma","pmids":["38862197"],"confidence":"Medium","gaps":["Direct mechanism by which LGALS1 induces CCR2/ADAM15/β-integrin not established","Receptor on tumor cells not identified"]},{"year":2024,"claim":"Connected LGALS1 to fatty acid metabolism and immune evasion in leukemia stem cells, extending its role beyond signaling to metabolic regulation.","evidence":"LGALS1 knockdown in vitro and in vivo with flow cytometry for CD8+ T/NK cells and lipid accumulation assays","pmids":["38965225"],"confidence":"Medium","gaps":["Mechanistic link between LGALS1 and lipid metabolism not defined","Secreted vs intracellular role unresolved"]},{"year":2024,"claim":"Implicated LGALS1 as an activator of PI3K/AKT signaling in a non-cancer fibrotic context.","evidence":"LGALS1 overexpression in TCMK-1 cells with PI3K/AKT phosphorylation Western blots in a TGF-β fibrosis model","pmids":["38967135"],"confidence":"Low","gaps":["Single overexpression experiment without loss-of-function or mutagenesis","No direct interaction defining how LGALS1 engages PI3K/AKT"]},{"year":2026,"claim":"Resolved a post-translational mechanism controlling LGALS1 stability, showing phosphorylation-state-dependent degradation governs its immunosuppressive output.","evidence":"Mass spectrometry, reciprocal co-IP, phosphomimetic mutagenesis of Ser8/Thr58, and mouse models","pmids":["41611244"],"confidence":"High","gaps":["Kinase that phosphorylates Ser8/Thr58 not identified","Degradation machinery (E3 ligase) not defined"]},{"year":2026,"claim":"Identified the endothelial receptor CD276 as a direct high-affinity LGALS1 partner and mapped the glycan-dependent interaction driving angiogenesis.","evidence":"Human proteome microarray, co-IP, glycosylation-site mutagenesis (N433), and Cd276-/- and Lgals1-/- mouse models in bladder cancer","pmids":["42230983"],"confidence":"High","gaps":["Whether CD276 binding mediates LGALS1's immune effects vs angiogenesis alone not separated","MAP4-to-PI3K/AKT coupling mechanism not detailed"]},{"year":2026,"claim":"Placed LGALS1 within a CAF-to-tumor transcriptional circuit that de-represses its expression and enables T cell suppression.","evidence":"miR-181b-5p/SEC24C/STING/YY1 pathway dissection with reporter and expression assays, T cell suppression assays, and mouse models in pancreatic cancer","pmids":["41713839"],"confidence":"Medium","gaps":["Role of SUSD2 in LGALS1 secretion mechanistically thin","Many steps in one model not independently validated"]},{"year":null,"claim":"The receptor(s) and molecular mechanism by which secreted LGALS1 suppresses CD8+ T and NK cells, and how its secreted lectin activity connects to the intracellular signaling and RNA-binding functions ascribed to it, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No defined T cell receptor for LGALS1 in the corpus","Intracellular vs extracellular functional separation untested","No structural model of LGALS1 in complex with any partner"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3]}],"complexes":[],"partners":["CD276","DUSP22"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P09382","full_name":"Galectin-1","aliases":["14 kDa laminin-binding protein","HLBP14","14 kDa lectin","Beta-galactoside-binding lectin L-14-I","Galaptin","HBL","HPL","Lactose-binding lectin 1","Lectin galactoside-binding soluble 1","Putative MAPK-activating protein PM12","S-Lac lectin 1"],"length_aa":135,"mass_kda":14.7,"function":"Lectin that binds beta-galactoside and a wide array of complex carbohydrates. Plays a role in regulating apoptosis, cell proliferation and cell differentiation. Inhibits CD45 protein phosphatase activity and therefore the dephosphorylation of Lyn kinase. Strong inducer of T-cell apoptosis. Plays a negative role in Th17 cell differentiation via activation of the receptor CD69 (PubMed:24752896)","subcellular_location":"Secreted, extracellular space, extracellular matrix; Cytoplasm; Secreted","url":"https://www.uniprot.org/uniprotkb/P09382/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LGALS1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000100097","cell_line_id":"CID000941","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"LSM14B","stoichiometry":4.0},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"PPIF","stoichiometry":0.2},{"gene":"NDUFA3","stoichiometry":0.2},{"gene":"TRAP1","stoichiometry":0.2},{"gene":"ACADM","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000941","total_profiled":1310},"omim":[{"mim_id":"615825","title":"SUSHI DOMAIN-CONTAINING PROTEIN 2; SUSD2","url":"https://www.omim.org/entry/615825"},{"mim_id":"609799","title":"NIMA-RELATED KINASE 8; NEK8","url":"https://www.omim.org/entry/609799"},{"mim_id":"602229","title":"SRY-BOX 10; SOX10","url":"https://www.omim.org/entry/602229"},{"mim_id":"600615","title":"LECTIN, GALACTOSIDE-BINDING, SOLUBLE, 7; LGALS7","url":"https://www.omim.org/entry/600615"},{"mim_id":"150571","title":"LECTIN, GALACTOSIDE-BINDING, SOLUBLE, 2; LGALS2","url":"https://www.omim.org/entry/150571"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LGALS1"},"hgnc":{"alias_symbol":["GBP"],"prev_symbol":[]},"alphafold":{"accession":"P09382","domains":[{"cath_id":"2.60.120.200","chopping":"4-133","consensus_level":"high","plddt":97.6612,"start":4,"end":133}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P09382","model_url":"https://alphafold.ebi.ac.uk/files/AF-P09382-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P09382-F1-predicted_aligned_error_v6.png","plddt_mean":96.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LGALS1","jax_strain_url":"https://www.jax.org/strain/search?query=LGALS1"},"sequence":{"accession":"P09382","fasta_url":"https://rest.uniprot.org/uniprotkb/P09382.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P09382/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P09382"}},"corpus_meta":[{"pmid":"30613962","id":"PMC_30613962","title":"Immunogenomic analysis reveals LGALS1 contributes to the immune heterogeneity and immunosuppression in glioma.","date":"2019","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30613962","citation_count":92,"is_preprint":false},{"pmid":"35180865","id":"PMC_35180865","title":"NCAPG promotes the oncogenesis and progression of non-small cell lung cancer cells through upregulating LGALS1 expression.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35180865","citation_count":41,"is_preprint":false},{"pmid":"25687228","id":"PMC_25687228","title":"Functional variants regulating LGALS1 (Galectin 1) expression affect human susceptibility to influenza A(H7N9).","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25687228","citation_count":38,"is_preprint":false},{"pmid":"30159048","id":"PMC_30159048","title":"Upregulation of LGALS1 is associated with oral cancer metastasis.","date":"2018","source":"Therapeutic advances in medical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30159048","citation_count":30,"is_preprint":false},{"pmid":"32590026","id":"PMC_32590026","title":"LGALS1 acts as a pro-survival molecule in AML.","date":"2020","source":"Biochimica et biophysica acta. 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function","date":"2025-01-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.07.631757","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.10.632345","title":"Generation of a T cell receptor, cytokine and cell repertoire synovial fluid atlas to define commonalities and dissimilarities between arthritic diseases through systems immunology approaches","date":"2025-01-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.10.632345","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16303,"output_tokens":2995,"usd":0.046917,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10354,"output_tokens":3552,"usd":0.070285,"stage2_stop_reason":"end_turn"},"total_usd":0.117202,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2026,\n      \"finding\": \"DUSP22 binds to LGALS1 and dephosphorylates it at Ser8 and Thr58 residues, leading to LGALS1 protein degradation and subsequent alleviation of LGALS1-mediated immunosuppression; this was confirmed by mass spectrometry, co-immunoprecipitation, and phosphomimetic mutant experiments.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, phosphomimetic mutagenesis, flow cytometry, mouse models\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal Co-IP, phosphomimetic mutagenesis confirming specific sites, in vivo validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"41611244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Tumor cell-secreted LGALS1 binds with high affinity to CD276 (B7-H3) on endothelial cells, with the interaction mediated by N-linked glycosylation at the N433 site within the D4 domain of CD276; this interaction activates MAP4-dependent PI3K/AKT signaling to promote angiogenesis and bladder cancer progression.\",\n      \"method\": \"Human proteome microarray, co-immunoprecipitation, glycosylation site mutagenesis, subcutaneous and orthotopic mouse models, Cd276−/− and Lgals1−/− mouse models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — proteome microarray binding identification, mutagenesis of interaction site, validated in knockout mouse models, multiple orthogonal methods\",\n      \"pmids\": [\"42230983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LGALS1 knockdown in highly invasive oral cancer cells inactivates p38 MAPK phosphorylation, downregulates MMP-9, and inhibits epithelial-mesenchymal transition (EMT), establishing LGALS1 as an upstream regulator of the p38 MAPK/MMP-9/EMT axis in oral cancer metastasis.\",\n      \"method\": \"siRNA knockdown, in vitro migration/invasion assays, in vivo mouse metastasis model, western blot for p38 MAPK phosphorylation and MMP-9\",\n      \"journal\": \"Therapeutic advances in medical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype and pathway placement, in vitro and in vivo, single lab\",\n      \"pmids\": [\"30159048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LGALS1+ fibroblasts promote proliferation and migration of intrahepatic cholangiocarcinoma cells by upregulating CCR2, ADAM15, and β-integrin expression; silencing LGALS1 in cancer-associated fibroblasts suppressed tumor cell migration and invasion in vitro and tumor formation in vivo.\",\n      \"method\": \"Single-cell RNA sequencing, siRNA knockdown in CAFs, in vitro co-culture migration/invasion assays, in vivo tumor formation model\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — scRNA-seq identification, functional KD with defined phenotype and downstream targets, in vivo validation, single lab\",\n      \"pmids\": [\"38862197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CAF-derived miR-181b-5p targets SEC24C in pancreatic cancer cells to inhibit STING phosphorylation, which blocks YY1 nuclear translocation and de-represses LGALS1 transcription; upregulated LGALS1 is then secreted via SUSD2 assistance to suppress CD8+ T cell function and induce apoptosis.\",\n      \"method\": \"In vitro T cell suppression assays, in vivo mouse models, pathway inhibition experiments, mechanistic reporter and expression assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pathway placed by multiple mechanistic steps with in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"41713839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LGALS1 knockdown in AML cell lines sensitized them to BCL2 inhibitor ABT-737, and in vivo shRNA-mediated LGALS1 suppression in a murine OCI-AML3 xenograft model significantly prolonged survival, demonstrating a pro-survival function of LGALS1 in AML.\",\n      \"method\": \"shRNA knockdown, murine xenograft model, RNASeq gene expression profiling\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo KD with survival phenotype, RNASeq pathway profiling, single lab\",\n      \"pmids\": [\"32590026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Knockdown of LGALS1 in glioblastoma remodels the immunosuppressive microenvironment by downregulating M2 macrophages and myeloid-derived suppressor cells (MDSCs) and inhibiting immunosuppressive cytokines, placing LGALS1 as a regulator of myeloid cell polarization in the tumor microenvironment.\",\n      \"method\": \"LGALS1 knockdown in vitro and in vivo, flow cytometry for immune cell populations, cytokine measurement\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vitro and in vivo KD with defined immunological phenotypes, single lab\",\n      \"pmids\": [\"30613962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGALS1 overexpression in kidney tubular TCMK-1 cells increased fibrosis markers and upregulated PI3K and AKT phosphorylation, establishing LGALS1 as an activator of the PI3K/AKT signaling pathway in renal fibrosis.\",\n      \"method\": \"LGALS1 overexpression in TCMK-1 cells, Western blot for PI3K/AKT phosphorylation, TGF-β-induced fibrosis model\",\n      \"journal\": \"Renal failure\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment with western blot, single lab, no mutagenesis or reconstitution\",\n      \"pmids\": [\"38967135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGALS1 repression in AML cells inhibited proliferation, enhanced apoptosis, decreased lipid accumulation, and curbed AML progression in vivo; LGALS1 repression also reduced CD8+ T and NK cell suppression in vivo, linking LGALS1 to fatty acid metabolism and immune evasion in leukemia stem cells.\",\n      \"method\": \"LGALS1 knockdown in vitro and in vivo, flow cytometry for immune cells, lipid accumulation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vitro and in vivo KD with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"38965225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LGALS1 silencing in NSCLC A549 cells altered alternative splicing of BCAP29, CSNKIE, and MDFIC and regulated expression of ELMO1, KCNJ2, and HSPA6, with LGALS1 overexpression rescuing these changes, identifying LGALS1 as an RNA-binding protein regulating alternative splicing in NSCLC.\",\n      \"method\": \"siRNA knockdown, RNA sequencing, RT-qPCR, LGALS1 overexpression rescue\",\n      \"journal\": \"Advances in clinical and experimental medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RNA-seq with partial RT-qPCR validation, no direct RBP binding assay confirming mechanism\",\n      \"pmids\": [\"37341175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-22-3p directly binds to LGALS1 mRNA (confirmed by dual luciferase assay); overexpression of miR-22-3p in melanoma cells decreased LGALS1 expression, reduced VIM and SNAI2, increased CDH1, and inhibited EMT, establishing LGALS1 as a target of miR-22-3p-mediated EMT regulation in melanoma.\",\n      \"method\": \"Dual luciferase reporter assay, miR-22-3p overexpression, western blot for EMT markers, cell viability and apoptosis assays\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual luciferase confirming direct binding, functional overexpression with downstream marker validation, single lab\",\n      \"pmids\": [\"36224027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In glioblastoma, TGFBR2 expression in mesenchymal glioma stem cells drives a 6-gene immunosuppressive Treg-like signature that includes LGALS1 (galectin-1), and TGFBR2 inhibition reversed this signature and restored CD4+ and CD8+ T cell function.\",\n      \"method\": \"Transgenic TGFBR2 expression, shRNA-based TGFBR2 inhibition, single-cell sequencing, T cell viability assays\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — LGALS1 identified as part of a multi-gene signature downstream of TGFBR2, not specifically validated for LGALS1 alone; preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"LGALS1 (Galectin-1) is a secreted lectin and intracellular signaling protein that promotes tumor immune evasion by suppressing CD8+ T cells and promoting M2 macrophage/MDSC polarization; its stability is regulated by DUSP22-mediated dephosphorylation at Ser8/Thr58 (leading to degradation), and it drives pro-tumorigenic signaling through binding CD276 on endothelial cells to activate MAP4/PI3K/AKT-dependent angiogenesis, acting downstream of p38 MAPK/MMP-9/EMT pathways in metastasis, and functioning as an RNA-binding protein that regulates alternative splicing in cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LGALS1 (Galectin-1) is a secreted lectin that functions as a central driver of tumor immune evasion and pro-tumorigenic signaling across multiple cancers [#1, #6]. Tumor- and fibroblast-derived LGALS1 reshapes the immune microenvironment, suppressing CD8+ T cell and NK cell function and reducing M2 macrophage and myeloid-derived suppressor cell populations upon its loss [#6, #8]. Mechanistically, tumor-secreted LGALS1 binds with high affinity to CD276 (B7-H3) on endothelial cells through N-linked glycosylation at N433 in the CD276 D4 domain, activating MAP4-dependent PI3K/AKT signaling to promote angiogenesis and bladder cancer progression [#1]. In addition, LGALS1 acts as an upstream activator of a p38 MAPK/MMP-9 axis that drives epithelial-mesenchymal transition and metastasis [#2], and in cancer-associated fibroblasts it promotes tumor cell proliferation and migration by upregulating CCR2, ADAM15, and \\u03b2-integrin [#3]. LGALS1 protein abundance is controlled post-translationally: DUSP22 binds and dephosphorylates LGALS1 at Ser8 and Thr58, triggering its degradation and relieving LGALS1-mediated immunosuppression [#0]. Its expression is further regulated through miRNA targeting, including direct binding by miR-22-3p [#10], and a CAF-derived miR-181b-5p/SEC24C/STING/YY1 axis that de-represses LGALS1 transcription [#4]. LGALS1 also confers a pro-survival, lipid-metabolism-linked phenotype in acute myeloid leukemia [#5, #8].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established LGALS1 as a functional upstream driver of metastasis rather than a passive marker, by placing it at the head of a defined signaling axis.\",\n      \"evidence\": \"siRNA knockdown in invasive oral cancer cells with migration/invasion assays, an in vivo metastasis model, and Western blot for p38 MAPK and MMP-9\",\n      \"pmids\": [\"30159048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not show direct molecular binding linking LGALS1 to p38 activation\", \"Mechanism of how a secreted lectin engages intracellular p38 signaling not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed LGALS1 controls the myeloid arm of the immunosuppressive tumor microenvironment, defining it as a regulator of M2 macrophage and MDSC polarization.\",\n      \"evidence\": \"LGALS1 knockdown in vitro and in vivo in glioblastoma with flow cytometry for immune populations and cytokine measurement\",\n      \"pmids\": [\"30613962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating myeloid polarization not identified\", \"Cannot distinguish secreted vs intracellular contributions\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated a cell-autonomous pro-survival role for LGALS1 in leukemia, linking it to apoptotic threshold and therapeutic sensitivity.\",\n      \"evidence\": \"shRNA knockdown in AML cell lines with ABT-737 sensitization and survival readout in a murine OCI-AML3 xenograft, plus RNASeq\",\n      \"pmids\": [\"32590026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link to BCL2-family apoptotic machinery not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified upstream transcriptional control of LGALS1 by miR-22-3p, connecting its expression level to EMT regulation in melanoma.\",\n      \"evidence\": \"Dual luciferase reporter assay confirming direct mRNA binding, miR-22-3p overexpression with EMT marker Western blots\",\n      \"pmids\": [\"36224027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish LGALS1's own downstream effector mechanism in melanoma\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Proposed an intracellular, non-lectin function for LGALS1 as an RNA-binding protein controlling alternative splicing.\",\n      \"evidence\": \"siRNA knockdown plus RNA-seq with RT-qPCR and overexpression rescue in NSCLC A549 cells\",\n      \"pmids\": [\"37341175\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct RBP binding assay (CLIP/EMSA) confirming physical RNA interaction\", \"Splicing targets validated only at expression level\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a stromal source of LGALS1 in cancer-associated fibroblasts and its downstream effectors driving tumor cell invasion.\",\n      \"evidence\": \"scRNA-seq identification with siRNA knockdown in CAFs, co-culture invasion assays, and in vivo tumor formation in cholangiocarcinoma\",\n      \"pmids\": [\"38862197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism by which LGALS1 induces CCR2/ADAM15/\\u03b2-integrin not established\", \"Receptor on tumor cells not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected LGALS1 to fatty acid metabolism and immune evasion in leukemia stem cells, extending its role beyond signaling to metabolic regulation.\",\n      \"evidence\": \"LGALS1 knockdown in vitro and in vivo with flow cytometry for CD8+ T/NK cells and lipid accumulation assays\",\n      \"pmids\": [\"38965225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between LGALS1 and lipid metabolism not defined\", \"Secreted vs intracellular role unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated LGALS1 as an activator of PI3K/AKT signaling in a non-cancer fibrotic context.\",\n      \"evidence\": \"LGALS1 overexpression in TCMK-1 cells with PI3K/AKT phosphorylation Western blots in a TGF-\\u03b2 fibrosis model\",\n      \"pmids\": [\"38967135\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single overexpression experiment without loss-of-function or mutagenesis\", \"No direct interaction defining how LGALS1 engages PI3K/AKT\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved a post-translational mechanism controlling LGALS1 stability, showing phosphorylation-state-dependent degradation governs its immunosuppressive output.\",\n      \"evidence\": \"Mass spectrometry, reciprocal co-IP, phosphomimetic mutagenesis of Ser8/Thr58, and mouse models\",\n      \"pmids\": [\"41611244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase that phosphorylates Ser8/Thr58 not identified\", \"Degradation machinery (E3 ligase) not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified the endothelial receptor CD276 as a direct high-affinity LGALS1 partner and mapped the glycan-dependent interaction driving angiogenesis.\",\n      \"evidence\": \"Human proteome microarray, co-IP, glycosylation-site mutagenesis (N433), and Cd276-/- and Lgals1-/- mouse models in bladder cancer\",\n      \"pmids\": [\"42230983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD276 binding mediates LGALS1's immune effects vs angiogenesis alone not separated\", \"MAP4-to-PI3K/AKT coupling mechanism not detailed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed LGALS1 within a CAF-to-tumor transcriptional circuit that de-represses its expression and enables T cell suppression.\",\n      \"evidence\": \"miR-181b-5p/SEC24C/STING/YY1 pathway dissection with reporter and expression assays, T cell suppression assays, and mouse models in pancreatic cancer\",\n      \"pmids\": [\"41713839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of SUSD2 in LGALS1 secretion mechanistically thin\", \"Many steps in one model not independently validated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor(s) and molecular mechanism by which secreted LGALS1 suppresses CD8+ T and NK cells, and how its secreted lectin activity connects to the intracellular signaling and RNA-binding functions ascribed to it, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No defined T cell receptor for LGALS1 in the corpus\", \"Intracellular vs extracellular functional separation untested\", \"No structural model of LGALS1 in complex with any partner\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD276\", \"DUSP22\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}