{"gene":"LGALS1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1995,"finding":"Galectin-1 (LGALS1 protein) induces apoptosis of activated human T cells and T leukemia cell lines. The apoptotic effect requires expression of CD45, is decreased when N-glycan elongation is blocked by swainsonine, and is potentiated by inhibition of O-glycan elongation, demonstrating that specific glycan structures on target cells govern galectin-1-mediated cell death. Endothelial cells expressing galectin-1 could similarly induce apoptosis of bound T cells.","method":"Cell-based apoptosis assays with activated vs. resting T cells, glycosylation inhibitors (swainsonine), antibody blocking of CD45, endothelial cell co-culture","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, replicated in multiple cell types, foundational paper with >900 citations","pmids":["7501023"],"is_preprint":false},{"year":1999,"finding":"Galectin-1 binding to activated T cells induces redistribution of specific surface glycoproteins (CD45, CD43, CD7) into segregated membrane microdomains. CD45 and CD3 co-localize on large apoptotic blebs with externalized phosphatidylserine, while CD7 and CD43 localize to separate patches. This receptor segregation is required for galectin-1-triggered apoptosis signaling, as it was not observed in cells resistant to galectin-1-induced death.","method":"Confocal microscopy, immunofluorescence co-localization, annexin V staining for phosphatidylserine externalization in T cell lines and primary thymocytes","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — direct imaging of membrane reorganization with functional correlation, multiple cell types, >270 citations","pmids":["10490978"],"is_preprint":false},{"year":1998,"finding":"Beta-galactoside binding protein (betaGBP), the LGALS1 gene product, arrests activated T lymphocytes in S and G2/M phases of the cell cycle and up-regulates expression of both alpha- and beta-chains of the IFN-gamma receptor on activated T lymphoblasts, rendering them sensitive to IFN-gamma-induced apoptosis. These effects are independent of sugar binding, as saturating lactose does not block cell cycle arrest or IFN-gamma receptor up-regulation.","method":"Flow cytometry cell cycle analysis, FACS quantification of IFN-gamma receptor chains, lactose competition assay, proliferation assays with PHA-activated T cells and malignant T cell lines","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, sugar-independence established by competition assay, directly identifies LGALS1 product","pmids":["9725202"],"is_preprint":false},{"year":1999,"finding":"BetaGBP (LGALS1 product) causes S/G2 growth arrest in both normal and leukemic T cells, but selectively induces apoptosis in leukemic T cells. Apoptosis in leukemic cells correlates with decreased Bcl-2 and consequent predominance of Bax, whereas normal T cells that survive maintain Bcl-2:Bax ratio unchanged, indicating the Bcl-2/Bax balance governs differential apoptotic sensitivity.","method":"Flow cytometry cell cycle analysis, western blot for Bcl-2 and Bax protein levels in normal vs. leukemic T cells","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — direct comparison of normal vs. leukemic cells with molecular mechanism (Bcl-2/Bax), single lab","pmids":["9886496"],"is_preprint":false},{"year":1999,"finding":"BetaGBP (LGALS1 product) induces cell cycle block prior to G2 entry followed by progressive apoptotic death in three human mammary cancer cell lines with different oncogenic potential, estrogen receptor, and EGFR family expression status, suggesting a general mechanism not dependent on these specific markers.","method":"Flow cytometry cell cycle analysis, apoptosis assays in MCF-7, MDA-MB-231, and SK-BR-3 cell lines","journal":"European journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple cell lines with different molecular profiles tested, single lab","pmids":["10533482"],"is_preprint":false},{"year":2001,"finding":"Galectin-1 (LGALS1) selectively binds oncogenic H-Ras(12V) but not wild-type H-Ras, K-Ras(12V), or N-Ras(13V), forming a direct protein-protein complex (molecular weight equal to sum of both proteins). Galectin-1 promotes membrane anchorage of H-Ras(12V), increases Ras-GTP and active ERK, and drives cell transformation that is blocked by dominant-negative Ras. Galectin-1 antisense RNA abolishes membrane anchorage of GFP-H-Ras(12V). Farnesylthiosalicylic acid (FTS) disrupts H-Ras(12V)-galectin-1 interactions.","method":"Co-immunoprecipitation, molecular weight analysis of complex, GFP-Ras localization by fluorescence microscopy, antisense knockdown, dominant-negative Ras rescue, ERK activation assay, cell transformation assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including co-IP, localization, functional rescue, and pharmacological disruption; >327 citations","pmids":["11709720"],"is_preprint":false},{"year":2004,"finding":"Crystal structure of human galectin-1 defines the ligand-binding pocket structure and carbohydrate recognition domain. Single-site mutations C2S and R111H at sites distant from the carbohydrate recognition domain alter the presentation of the loop harboring Asp123 and shift key sugar-binding residues His52 and Trp68, reducing ligand affinity through increased entropic penalty. The positions of SH-groups restrict intramolecular disulfide bridge formation but the C2S mutant displays improved stability under oxidative conditions.","method":"X-ray crystallography, isothermal titration calorimetry for thermodynamic analysis of ligand binding","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure determination plus functional validation by calorimetry; >250 citations","pmids":["15476813"],"is_preprint":false},{"year":2004,"finding":"Targeted knockdown of galectin-1 (LGALS1) gene expression in tumor cells results in heightened T cell-mediated tumor rejection in vivo in syngeneic mice, identifying galectin-1 as a key mediator of tumor immune privilege. Mice that rejected Gal-1-deficient tumors subsequently resisted challenge with wild-type Gal-1-sufficient tumors, demonstrating generation of a lasting tumor-specific T cell response.","method":"Antisense RNA knockdown of Gal-1 in tumor cells, syngeneic mouse tumor challenge models, T cell functional assays, tumor re-challenge experiments","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 — in vivo loss-of-function with defined immune phenotype, re-challenge experiments, >440 citations","pmids":["15050916"],"is_preprint":false},{"year":2006,"finding":"Galectin-1 is essential for tumor angiogenesis. Galectin-1 is the receptor for the angiogenesis inhibitor anginex. Knockdown of galectin-1 in cultured endothelial cells inhibits cell proliferation and migration. In zebrafish, galectin-1 knockdown impairs vascular guidance and produces dysfunctional vessels. In gal-1-null mice, tumor growth is markedly impaired due to insufficient tumor angiogenesis, and tumors no longer respond to antiangiogenesis treatment by anginex.","method":"Pulldown/receptor identification for anginex, siRNA knockdown in endothelial cells, zebrafish morpholino knockdown with vascular imaging, syngeneic tumor implantation in gal-1-null knockout mice","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods in vitro and in vivo including genetic null mice and zebrafish; >398 citations","pmids":["17043243"],"is_preprint":false},{"year":2006,"finding":"Galectin-1 is a key effector of the suppressive function of CD4+CD25+ regulatory T cells (Tregs). Galectin-1 expression is upregulated in Tregs after activation. Blockade of galectin-1 binding significantly reduces the inhibitory effects of both human and mouse Tregs. CD4+CD25+ T cells from galectin-1-null mice show reduced regulatory activity.","method":"Gene expression analysis, antibody blockade of galectin-1 in suppression assays, Treg suppression assays using galectin-1-null mouse cells","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — antibody blockade plus genetic null mouse cells with functional suppression readout; >392 citations","pmids":["17110462"],"is_preprint":false},{"year":2014,"finding":"Galectin-1 (Gal-1) preserves angiogenesis in tumors refractory to anti-VEGF therapy by binding complex N-glycans on VEGFR2, activating VEGF-like signaling in a glycosylation-dependent manner. Vessels in anti-VEGF-refractory tumors exhibit glycosylation patterns that facilitate Gal-1-endothelial cell interactions, while sensitive tumors display α2-6-linked sialic acid that prevents Gal-1 binding. Interrupting β1-6GlcNAc branching in ECs or silencing tumor-derived Gal-1 converts refractory tumors to anti-VEGF-sensitive tumors.","method":"Lectin binding assays, siRNA knockdown of tumor Gal-1 and endothelial glycosyltransferases, tumor implantation in Gal-1-null mice, VEGFR2 signaling readouts, glycan analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic identification of VEGFR2 as Gal-1 receptor, multiple genetic manipulations, in vivo validation, >421 citations","pmids":["24529377"],"is_preprint":false},{"year":2012,"finding":"LGALS1 is identified as an mRNA-binding protein in human HeLa cells through systematic UV crosslinking-based mRNA interactome capture, revealing an unexpected RNA-binding activity for this galectin.","method":"UV crosslinking of proteins to mRNA followed by oligo(dT) capture and mass spectrometry (interactome capture)","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — unbiased genome-wide method, but LGALS1 is one of >860 proteins identified without specific functional follow-up","pmids":["22658674"],"is_preprint":false},{"year":2018,"finding":"LGALS1 knockdown in glioblastoma (GBM) cells remodels the immunosuppressive tumor microenvironment by downregulating M2 macrophage polarization and myeloid-derived suppressor cells (MDSCs) and inhibiting immunosuppressive cytokines, demonstrating that LGALS1 actively maintains immunosuppression in GBM.","method":"siRNA knockdown of LGALS1 in GBM cells with in vitro and in vivo assessment of immune cell composition (M2 macrophages, MDSCs) and cytokine profiling","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined immune phenotype readouts in vitro and in vivo, single lab","pmids":["30613962"],"is_preprint":false},{"year":2018,"finding":"LGALS1 silencing in highly invasive oral cancer cells suppresses p38 MAPK phosphorylation, downregulates MMP-9 expression, and inhibits epithelial-mesenchymal transition (EMT) markers, while its expression drives invasion through this p38 MAPK pathway.","method":"siRNA knockdown of LGALS1, wound healing assay, transwell invasion assay, western blot for p38 MAPK phosphorylation, MMP-9, and EMT markers, in vivo lung metastasis mouse model","journal":"Therapeutic advances in medical oncology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with pathway-level mechanistic readouts and in vivo validation, single lab","pmids":["30159048"],"is_preprint":false},{"year":2020,"finding":"LGALS1 acts as a pro-survival molecule in acute myeloid leukemia (AML). In vivo, shRNA suppression of LGALS1 in OCI-AML3 xenograft-bearing mice significantly extends survival. LGALS1 suppression affects distinct transcriptional programs in p53-WT (OCI-AML3) versus p53-mutant (THP-1) AML cell lines, with the p53 pathway prominently altered in OCI-AML3 cells.","method":"shRNA knockdown in xenograft mouse model, RNASeq gene expression profiling, comparison of p53-WT vs p53-mutant cell lines","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo xenograft model with survival endpoint plus transcriptomic pathway analysis, single lab","pmids":["32590026"],"is_preprint":false},{"year":2022,"finding":"NCAPG promotes NSCLC oncogenesis through upregulation of LGALS1 expression, and LGALS1 may directly interact with NCAPG. Transcriptome sequencing identified LGALS1 as a downstream mediator of NCAPG function in promoting initiation and progression of NSCLC.","method":"Transcriptome sequencing, TCGA database analysis, NCAPG knockdown in vitro and in vivo, Ncapg+/- mice with urethane-induced lung tumors, interaction studies between NCAPG and LGALS1","journal":"Molecular cancer","confidence":"Low","confidence_rationale":"Tier 3 — NCAPG-LGALS1 interaction suggested but not rigorously validated; LGALS1 role described as downstream without direct mechanistic proof","pmids":["35180865"],"is_preprint":false},{"year":2023,"finding":"LGALS1 in glioblastoma acts as a primary regulator of immunosuppression. LGALS1 knockout experiments in zebrafish xenograft models demonstrate that LGALS1 modulates GBM-associated macrophage (GAM) polarization and attraction. Single-cell RNA sequencing of GAM-GBM co-cultures revealed LGALS1-dependent molecular heterogeneity correlated with patient survival.","method":"Single-cell RNA sequencing, LGALS1 knockout experiments in orthotopic zebrafish xenograft models, immunohistochemistry on patient tumor samples, GAM-GBM co-culture systems","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockout in vivo model combined with single-cell transcriptomics and patient sample validation","pmids":["37791581"],"is_preprint":false},{"year":2024,"finding":"LGALS1 repression in AML cells and leukemia stem cells (LSCs) inhibits cell proliferation, enhances apoptosis, and decreases lipid accumulation in vitro. In vivo, LGALS1 repression curbs AML progression and lipid accumulation while increasing CD8+ T and NK cell counts, establishing LGALS1 as a regulator of lipid metabolism and immune evasion in LSCs.","method":"shRNA/siRNA knockdown in AML cell lines and LSCs, in vivo AML mouse model, lipid quantification assays, flow cytometry for CD8+ T and NK cells","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function in vitro and in vivo with multiple defined readouts, single lab","pmids":["38965225"],"is_preprint":false},{"year":2024,"finding":"LGALS1+ fibroblasts activate proliferation and migration of intrahepatic cholangiocarcinoma (ICC) tumor cells by upregulating CCR2, ADAM15, and β-integrin expression. Silencing LGALS1 in cancer-associated fibroblasts (CAFs) suppresses CAF-augmented tumor cell migration and invasion in vitro and tumor formation in vivo.","method":"Single-cell RNA sequencing, siRNA knockdown of LGALS1 in CAFs, in vitro migration/invasion assays, in vivo tumor formation models","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined molecular mediators (CCR2, ADAM15, β-integrin) and in vivo validation","pmids":["38862197"],"is_preprint":false},{"year":2024,"finding":"Lgals1 overexpression in kidney cells (TCMK-1) significantly increases fibrosis and upregulates PI3K and AKT phosphorylation activity. LGALS1/Lgals1 is overexpressed in CKD kidney interstitium and acts upstream of the PI3K/AKT signaling pathway to drive renal fibrosis.","method":"Overexpression of Lgals1 in TCMK-1 cells, PI3K and AKT phosphorylation assays, CKD mouse model (5/6 nephrectomy), fibrosis assessment","journal":"Renal failure","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function with pathway-level mechanistic readouts in vitro and in vivo CKD model","pmids":["38967135"],"is_preprint":false},{"year":2024,"finding":"LGALS1 functions as an RNA-binding protein that regulates alternative splicing (AS) events in NSCLC cells. LGALS1 silencing in A549 cells produces 433 upregulated and 481 downregulated AS events. LGALS1-regulated AS genes are enriched in apoptosis and ErbB signaling pathways. LGALS1 silencing alters the AS ratio of BCAP29 (decreased) and CSNKIE and MDFIC (increased), and these effects are rescued by LGALS1 overexpression.","method":"RNA sequencing after siRNA-mediated LGALS1 knockdown in A549 cells, RT-qPCR validation of AS events, LGALS1 overexpression rescue experiments","journal":"Advances in clinical and experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 — systematic transcriptomic analysis with rescue experiments confirming LGALS1-specific AS regulation","pmids":["37341175"],"is_preprint":false},{"year":2026,"finding":"DUSP22 binds LGALS1 directly and dephosphorylates it at Ser8 and Thr58 residues, leading to LGALS1 protein degradation. This dephosphorylation-dependent degradation of LGALS1 alleviates LGALS1-mediated immunosuppression and increases CD8+ T-cell infiltration in the tumor microenvironment. In breast cancer, LGALS1 expression negatively correlates with both DUSP22 levels and CD8+ T-cell infiltration.","method":"AP-MS protein interaction identification, co-immunoprecipitation validation, phosphomimetic mutant experiments identifying Ser8 and Thr58 as dephosphorylation sites, flow cytometry and IHC for CD8+ T-cell infiltration, in vivo mouse tumor models, analysis of bulk and scRNA-seq data","journal":"Journal for immunotherapy of cancer","confidence":"High","confidence_rationale":"Tier 1-2 — direct identification of phosphorylation sites by mutagenesis, Co-IP validation, in vivo functional consequences, multiple orthogonal methods","pmids":["41611244"],"is_preprint":false},{"year":2026,"finding":"In pancreatic cancer, CAF-derived miR-181b-5p inhibits STING phosphorylation in tumor cells, blocking YY1 nuclear translocation and de-repressing LGALS1 transcription. The upregulated LGALS1 is secreted (via SUSD2 assistance) and suppresses CD8+ T cell function and induces their apoptosis, establishing a stromal-immune axis linking STING pathway inhibition to LGALS1-mediated immunosuppression.","method":"miRNA overexpression/inhibition, STING pathway manipulation, YY1 localization assays, SUSD2 co-expression studies, CD8+ T cell functional assays, in vitro and in vivo tumor models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — pathway epistasis established through multiple genetic manipulations with defined mechanistic steps, single lab","pmids":["41713839"],"is_preprint":false},{"year":1993,"finding":"LGALS1 and LGALS2 (encoding L-14-I and L-14-II S-lac lectins) reside in close proximity on human chromosome 22q12-q13, suggesting a cluster of genes for lactose-binding proteins.","method":"Chromosomal mapping by in situ hybridization and linkage analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct chromosomal mapping experiment","pmids":["8449510"],"is_preprint":false},{"year":2022,"finding":"miR-22-3p directly binds to and suppresses LGALS1 mRNA (confirmed by dual luciferase reporter assay). Overexpression of miR-22-3p in melanoma cells decreases LGALS1 expression, reduces cell viability, decreases VIM and SNAI2, increases CDH1, and increases apoptosis, inhibiting EMT. Exosomes from mesenchymal stem cells loaded with miR-22-3p reproduce these effects.","method":"Dual luciferase reporter assay for miR-22-3p binding to LGALS1 3'UTR, miR-22-3p overexpression, western blot for EMT markers, cell viability assay, exosome-mediated delivery","journal":"Frontiers in bioscience","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding confirmed by luciferase assay with functional downstream validation, single lab","pmids":["36224027"],"is_preprint":false}],"current_model":"LGALS1 (Galectin-1) is a beta-galactoside-binding lectin that operates through both extracellular glycan-dependent mechanisms and intracellular protein-protein interactions: extracellularly, it induces apoptosis of activated T cells by binding specific glycoproteins (CD45, CD43, CD7) and driving their segregation into membrane microdomains in a glycan-dependent manner; it promotes tumor angiogenesis by binding complex N-glycans on VEGFR2 to activate VEGF-like signaling; and it mediates tumor immune privilege by suppressing T cell activity and serving as a key effector of regulatory T cell function; intracellularly, it selectively binds oncogenic H-Ras(12V) to stabilize its membrane anchorage and activate ERK-driven transformation, functions as an RNA-binding protein regulating alternative splicing, and is subject to phosphorylation at Ser8/Thr58 by DUSP22-mediated dephosphorylation leading to its degradation and relief of immunosuppression."},"narrative":{"teleology":[{"year":1993,"claim":"Chromosomal mapping placed LGALS1 at 22q12-q13 in a cluster with LGALS2, establishing the genomic context for this lectin family member.","evidence":"In situ hybridization and linkage analysis on human chromosomes","pmids":["8449510"],"confidence":"Medium","gaps":["No regulatory elements characterized at this locus","Functional significance of LGALS1-LGALS2 clustering unknown"]},{"year":1995,"claim":"The first major functional role of galectin-1 was established: it induces apoptosis of activated T cells in a glycan-dependent, CD45-requiring manner, revealing it as an extracellular death signal for immune cells.","evidence":"Cell-based apoptosis assays with glycosylation inhibitors and CD45 blocking antibodies in primary T cells and T leukemia lines","pmids":["7501023"],"confidence":"High","gaps":["Downstream intracellular death signaling pathway not defined","Structural basis of glycan selectivity unknown"]},{"year":1998,"claim":"Galectin-1 was shown to arrest T cells in S/G2M and upregulate IFN-γ receptor expression through a sugar-independent mechanism, demonstrating that its immunomodulatory activities extend beyond lectin-mediated apoptosis.","evidence":"Flow cytometry cell cycle analysis and FACS quantification of IFN-γ receptor with lactose competition in PHA-activated T cells","pmids":["9725202"],"confidence":"High","gaps":["Identity of the sugar-independent receptor or intracellular target unknown","Relationship between cell cycle arrest and apoptosis not fully resolved"]},{"year":1999,"claim":"The spatial mechanism of galectin-1-induced T cell death was elucidated: it triggers segregation of CD45, CD43, and CD7 into distinct membrane microdomains with phosphatidylserine externalization on apoptotic blebs, and differential Bcl-2/Bax balance governs susceptibility in leukemic versus normal T cells.","evidence":"Confocal immunofluorescence co-localization of surface glycoproteins, annexin V staining, and Bcl-2/Bax western blotting in normal and leukemic T cells","pmids":["10490978","9886496"],"confidence":"High","gaps":["Signaling intermediates connecting receptor segregation to Bcl-2 downregulation undefined","Whether receptor segregation is sufficient or merely correlated with death not tested"]},{"year":2001,"claim":"An intracellular lectin-independent function was discovered: galectin-1 selectively binds oncogenic H-Ras(12V) (not WT H-Ras, K-Ras, or N-Ras), stabilizes its membrane anchorage, and activates ERK to drive transformation.","evidence":"Co-immunoprecipitation, GFP-Ras localization, antisense knockdown, dominant-negative rescue, and transformation assays","pmids":["11709720"],"confidence":"High","gaps":["Structural basis for H-Ras(12V) selectivity over other Ras isoforms unknown","Physiological contexts where this interaction drives oncogenesis in patients not established"]},{"year":2004,"claim":"The crystal structure of galectin-1 defined the carbohydrate recognition domain architecture and revealed that distant mutations allosterically shift key sugar-binding residues, while in vivo loss-of-function identified galectin-1 as a mediator of tumor immune privilege.","evidence":"X-ray crystallography with ITC thermodynamic analysis; antisense knockdown in syngeneic mouse tumor models with T cell-mediated rejection and re-challenge","pmids":["15476813","15050916"],"confidence":"High","gaps":["No structure of galectin-1 in complex with full glycoprotein ligands","Mechanism by which tumor galectin-1 specifically suppresses antitumor T cells versus other immune cells not resolved"]},{"year":2006,"claim":"Galectin-1 was identified as essential for tumor angiogenesis (serving as the receptor for anginex) and as a critical effector of regulatory T cell suppressive function, broadening its role from direct T cell killing to vascular and Treg biology.","evidence":"Anginex pulldown/receptor identification, siRNA in endothelial cells, zebrafish morpholino, gal-1-null mouse tumor models; antibody blockade and gal-1-null Treg suppression assays","pmids":["17043243","17110462"],"confidence":"High","gaps":["Endothelial receptor(s) mediating galectin-1 angiogenic signaling not yet identified at this point","Whether Treg-derived galectin-1 acts in trans on effector T cells or in cis on Tregs not distinguished"]},{"year":2012,"claim":"Unbiased mRNA interactome capture identified galectin-1 as an RNA-binding protein, suggesting a previously unrecognized intracellular function beyond lectin and Ras-binding activities.","evidence":"UV crosslinking and oligo(dT) capture followed by mass spectrometry in HeLa cells","pmids":["22658674"],"confidence":"Medium","gaps":["No specific RNA targets or functional consequences identified at this stage","RNA-binding domain not mapped"]},{"year":2014,"claim":"The molecular basis of galectin-1-driven tumor angiogenesis was resolved: it binds complex N-glycans on VEGFR2 to activate VEGF-like signaling, and α2-6 sialylation blocks this interaction, explaining anti-VEGF therapy resistance.","evidence":"Lectin binding, siRNA of tumor galectin-1 and endothelial glycosyltransferases, gal-1-null mouse tumor models, VEGFR2 signaling assays","pmids":["24529377"],"confidence":"High","gaps":["Whether galectin-1 engages additional endothelial receptors beyond VEGFR2 not excluded","Therapeutic strategies to block galectin-1-VEGFR2 interaction in patients not validated"]},{"year":2018,"claim":"Galectin-1 was shown to drive tumor cell invasion via p38 MAPK/MMP-9/EMT signaling and to maintain immunosuppressive tumor microenvironments by promoting M2 macrophage polarization and MDSC accumulation in glioblastoma.","evidence":"siRNA knockdown with western blot for p38/MMP-9/EMT markers and in vivo metastasis models; LGALS1 knockdown in GBM cells with immune cell composition and cytokine profiling","pmids":["30159048","30613962"],"confidence":"Medium","gaps":["Direct versus indirect effects of galectin-1 on macrophage polarization not delineated","Whether p38 MAPK activation requires extracellular glycan binding or intracellular interaction unknown"]},{"year":2022,"claim":"miR-22-3p was confirmed as a direct post-transcriptional suppressor of LGALS1 mRNA, and its delivery reverses EMT in melanoma, establishing a regulatory axis controlling galectin-1 expression.","evidence":"Dual luciferase reporter assay for miR-22-3p binding to LGALS1 3′UTR, miR-22-3p overexpression with EMT marker and apoptosis readouts","pmids":["36224027"],"confidence":"Medium","gaps":["Whether miR-22-3p regulation of LGALS1 operates in non-melanoma contexts untested","Other miRNAs targeting LGALS1 not systematically evaluated"]},{"year":2023,"claim":"Galectin-1's role as a primary immunosuppressive regulator in GBM was refined at single-cell resolution, showing it controls GBM-associated macrophage molecular heterogeneity correlated with patient survival.","evidence":"LGALS1 knockout in zebrafish orthotopic xenografts, single-cell RNA sequencing of GAM-GBM co-cultures, patient tissue immunohistochemistry","pmids":["37791581"],"confidence":"Medium","gaps":["Causal versus correlative relationship between LGALS1-dependent GAM states and survival not formally tested","Whether findings from zebrafish xenografts translate to mammalian immune microenvironment unclear"]},{"year":2024,"claim":"The RNA-binding function of galectin-1 was functionally validated: it regulates hundreds of alternative splicing events in NSCLC cells, with specific targets (BCAP29, CSNK1E, MDFIC) confirmed by rescue experiments, and it promotes AML progression partly through lipid metabolism regulation and PI3K/AKT-driven renal fibrosis.","evidence":"RNA-seq after LGALS1 siRNA with overexpression rescue in A549 cells; shRNA in AML xenograft models with lipid and immune readouts; Lgals1 overexpression in kidney cells with PI3K/AKT phosphorylation assays and CKD mouse model","pmids":["37341175","38965225","38967135"],"confidence":"Medium","gaps":["RNA-binding domain of galectin-1 not mapped","Whether splicing regulation is direct (RNA contact) or indirect (signaling-mediated) not resolved","PI3K/AKT activation mechanism by galectin-1 not defined"]},{"year":2026,"claim":"A post-translational control mechanism was identified: DUSP22 directly dephosphorylates galectin-1 at Ser8 and Thr58, triggering its degradation and relieving immunosuppression with increased CD8+ T cell infiltration; separately, CAF-derived miR-181b-5p suppresses STING/YY1 signaling to de-repress LGALS1 transcription in pancreatic cancer.","evidence":"AP-MS, co-IP, phosphomimetic mutagenesis, in vivo mouse tumor models with flow cytometry for CD8+ T cells; miRNA manipulation with STING pathway epistasis and CD8+ T cell functional assays","pmids":["41611244","41713839"],"confidence":"High","gaps":["Kinase(s) responsible for Ser8/Thr58 phosphorylation not identified","Whether DUSP22-mediated degradation occurs via proteasomal or lysosomal pathway unknown","Generalizability of STING-YY1-LGALS1 axis beyond pancreatic cancer untested"]},{"year":null,"claim":"Key unresolved questions include the structural basis for galectin-1's selectivity for H-Ras(12V) over other Ras isoforms, the identity and mapping of its RNA-binding domain, the kinase(s) that phosphorylate Ser8/Thr58, and whether its glycan-dependent and glycan-independent immunomodulatory activities operate through shared or distinct downstream signaling cascades.","evidence":"","pmids":[],"confidence":"Low","gaps":["No co-crystal structure with H-Ras(12V)","RNA-binding domain unmapped","Phosphorylating kinase unknown","Glycan-dependent versus glycan-independent signaling convergence untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1,6,10]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,10]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,10]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[11,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,9,21]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,8,9,10,22]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,20]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,7,9,12,16,17,21,22]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,3,4,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,10,13,19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,8,10,14]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[11,20]}],"complexes":[],"partners":["HRAS","VEGFR2","CD45","CD43","CD7","DUSP22","SUSD2"],"other_free_text":[]},"mechanistic_narrative":"Galectin-1 (LGALS1) is a β-galactoside-binding lectin that functions as a central immunomodulatory and pro-tumorigenic effector through both extracellular glycan-dependent and intracellular protein–protein interaction mechanisms. Extracellularly, it induces apoptosis of activated T cells by binding glycoproteins CD45, CD43, and CD7 and driving their segregation into distinct membrane microdomains [PMID:7501023, PMID:10490978], suppresses antitumor immunity as a key effector of regulatory T cell function [PMID:17110462], promotes tumor angiogenesis by engaging complex N-glycans on VEGFR2 to activate VEGF-like signaling [PMID:24529377], and its phosphorylation at Ser8/Thr58 is regulated by DUSP22-mediated dephosphorylation leading to its degradation and relief of immunosuppression [PMID:41611244]. Intracellularly, it selectively binds oncogenic H-Ras(12V) to stabilize its membrane anchorage and activate ERK-driven transformation [PMID:11709720], and regulates alternative splicing as an RNA-binding protein [PMID:37341175, PMID:22658674]. The crystal structure reveals a carbohydrate recognition domain in which distant mutations allosterically alter sugar-binding residue geometry and reduce ligand affinity [PMID:15476813]."},"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 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methods","url":"https://pubmed.ncbi.nlm.nih.gov/22863883","citation_count":273,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15476813","id":"PMC_15476813","title":"Growth-regulatory human galectin-1: crystallographic characterisation of the structural changes induced by single-site mutations and their impact on the thermodynamics of ligand binding.","date":"2004","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15476813","citation_count":250,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25819524","id":"PMC_25819524","title":"Galectin expression in cancer diagnosis and prognosis: A systematic review.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25819524","citation_count":235,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50277,"output_tokens":4496,"usd":0.109135},"stage2":{"model":"claude-opus-4-6","input_tokens":7255,"output_tokens":2720,"usd":0.156413},"total_usd":0.644912,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":61289,"output_tokens":7759,"usd":0.150126},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":10540,"output_tokens":4005,"usd":0.229238}},"stage1_raw":"Looking at the corpus, I need to identify papers about LGALS1 (Galectin-1, the beta-galactoside-binding lectin encoded by the LGALS1 gene). Many papers in this corpus are about other proteins named \"GBP\" (guanylate-binding proteins, growth-blocking peptides, glucose-binding proteins, etc.) and are not relevant to LGALS1. Let me extract only findings about LGALS1/Galectin-1.\n\nRelevant papers:\n- PMID:9725202 — beta-GBP (LGALS1 product) effects on T cell cycle and IFN-γR\n- PMID:9886496 — betaGBP cell cycle arrest in T cells, apoptosis via Bcl-2/Bax\n- PMID:10533482 — betaGBP cell cycle block and apoptosis in mammary cancer cells\n- PMID:8449510 — chromosomal mapping of LGALS1 and LGALS2\n- PMID:30613962 — LGALS1 knockdown remodels GBM immunosuppressive microenvironment\n- PMID:30159048 — LGALS1 in oral cancer, p38 MAPK/MMP-9/EMT pathway\n- PMID:32590026 — LGALS1 pro-survival in AML\n- PMID:35180865 — NCAPG upregulates LGALS1 in NSCLC\n- PMID:25687228 — LGALS1 variants affect susceptibility to H7N9\n- PMID:37791581 — LGALS1 as immunosuppression regulator in GBM\n- PMID:38965225 — LGALS1 in AML stem cells, lipid metabolism\n- PMID:36224027 — miR-22-3p targets LGALS1, regulates EMT in melanoma\n- PMID:38967135 — Lgals1/PI3K/AKT signaling in renal fibrosis\n- PMID:41611244 — DUSP22 dephosphorylates LGALS1 at Ser8/Thr58, leading to degradation\n- PMID:41713839 — CAF-derived miR-181b-5p/STING/LGALS1 pathway in pancreatic cancer\n- PMID:38862197 — LGALS1+ fibroblasts promote ICC via CCR2/ADAM15/β-integrin\n- PMID:37415637 — LGALS1 regulates cell adhesion in OC via ECM/focal adhesion\n- PMID:35872012 — LGALS1 expression/methylation in ALS\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Beta-galactoside-binding protein (betaGBP), the LGALS1 gene product, arrests activated human T lymphocytes in S and G2/M phases of the cell cycle and up-regulates expression of both alpha- and beta-chains of the IFN-γ receptor on the T lymphocyte membrane, rendering them sensitive to IFN-γ-induced apoptosis; these effects are independent of the protein's sugar-binding activity.\",\n      \"method\": \"Cell cycle analysis (flow cytometry), IFN-γR surface expression assay, lactose competition experiments in primary human T lymphocytes and malignant T cell lines\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean functional KD/OE with defined cellular phenotype; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"9725202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"LGALS1-encoded betaGBP causes S/G2 growth arrest in both normal and leukemic T cells; in leukemic T cells (but not normal T lymphocytes), arrest is followed by apoptosis associated with decreased Bcl-2 and consequent predominance of Bax, implicating the Bcl-2/Bax ratio as the mechanism of selective apoptosis induction.\",\n      \"method\": \"Flow cytometry (cell cycle analysis), western blot for Bcl-2 and Bax in normal and leukemic T cell lines treated with exogenous betaGBP\",\n      \"journal\": \"Journal of Cellular Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined molecular mechanism with multiple cell types; single lab\",\n      \"pmids\": [\"9886496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"betaGBP (LGALS1 product) induces cell cycle block prior to G2 entry followed by progressive apoptotic death in human mammary cancer cell lines (including those with differing oncogenic potential and receptor expression), suggesting a general anti-proliferative mechanism in epithelial cancer cells.\",\n      \"method\": \"Flow cytometry cell cycle analysis, clonogenic survival assays on three human mammary cancer cell lines treated with exogenous betaGBP\",\n      \"journal\": \"European Journal of Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method category, no molecular pathway placement\",\n      \"pmids\": [\"10533482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"LGALS1 and LGALS2 (encoding the S-lac lectins L-14-I and L-14-II) reside in close proximity on human chromosome 22q12-q13, suggesting a gene cluster for lactose-binding proteins.\",\n      \"method\": \"Chromosomal mapping (somatic cell hybrid analysis and in situ hybridization)\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct chromosomal mapping experiment; single lab but standard methodology\",\n      \"pmids\": [\"8449510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Knockdown of LGALS1 in highly invasive oral cancer cells suppresses cell growth, migration, wound healing, and invasion in vitro, and dramatically inhibits lung metastasis in vivo; mechanistically, LGALS1 promotes invasion via p38 MAPK phosphorylation, upregulation of MMP-9, and induction of epithelial-mesenchymal transition (EMT), all of which are reversed by siRNA-mediated LGALS1 silencing.\",\n      \"method\": \"siRNA knockdown, wound healing assay, Transwell migration/invasion, in vivo mouse lung metastasis model, western blot for p38 MAPK, MMP-9, and EMT markers\",\n      \"journal\": \"Therapeutic Advances in Medical Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific pathway readout, in vitro and in vivo validation; single lab\",\n      \"pmids\": [\"30159048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Knockdown of LGALS1 in glioblastoma (GBM) remodels the immunosuppressive tumor microenvironment by downregulating M2 macrophages and myeloid-derived suppressor cells (MDSCs) and inhibiting immunosuppressive cytokines, establishing LGALS1 as a key mediator of GBM immunosuppression.\",\n      \"method\": \"siRNA-mediated LGALS1 knockdown in GBM cells, flow cytometry for M2 macrophages and MDSCs, cytokine profiling; in vitro and in vivo experiments\",\n      \"journal\": \"International Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular immune phenotype; single lab\",\n      \"pmids\": [\"30613962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LGALS1 acts as a pro-survival molecule in acute myeloid leukemia (AML); shRNA suppression of LGALS1 in OCI-AML3 cells significantly prolonged survival in an in vivo xenograft model, and LGALS1 suppression sensitized AML cells to BCL2 inhibitor ABT-737, implicating LGALS1 in pro-survival signaling in AML.\",\n      \"method\": \"shRNA knockdown, in vivo mouse xenograft survival model, RNASeq gene expression profiling, drug sensitivity assays\",\n      \"journal\": \"Biochimica et Biophysica Acta – Molecular Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with defined survival phenotype; single lab, multiple methods\",\n      \"pmids\": [\"32590026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NCAPG promotes NSCLC oncogenesis and progression by upregulating LGALS1 expression; transcriptome sequencing and co-immunoprecipitation data indicate a direct interaction between NCAPG and LGALS1, placing LGALS1 downstream of NCAPG in lung cancer progression.\",\n      \"method\": \"Transcriptome sequencing, TCGA database analysis, siRNA knockdown, in vitro/in vivo tumor growth assays, co-immunoprecipitation for NCAPG-LGALS1 interaction\",\n      \"journal\": \"Molecular Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP, single lab; interaction claim requires further validation\",\n      \"pmids\": [\"35180865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-22-3p directly binds the LGALS1 mRNA 3'UTR (validated by dual luciferase assay) and suppresses LGALS1 expression in melanoma cells, leading to decreased EMT markers (VIM, SNAI2) and increased CDH1, reduced cell viability, and increased apoptosis; exosomes from mesenchymal stem cells loaded with miR-22-3p recapitulate these effects.\",\n      \"method\": \"Dual luciferase reporter assay, miR-22-3p overexpression, western blot for EMT markers, flow cytometry for apoptosis, exosome-mediated delivery\",\n      \"journal\": \"Frontiers in Bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding validated by luciferase assay plus functional downstream phenotype; single lab\",\n      \"pmids\": [\"36224027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGALS1 repression in AML cells inhibits AML cell and leukemia stem cell (LSC) proliferation, enhances apoptosis, decreases lipid accumulation in vitro, and curbs AML progression, lipid accumulation, and CD8+T/NK cell suppression in vivo, identifying LGALS1 as a regulator of fatty acid metabolism and immune evasion in AML LSCs.\",\n      \"method\": \"shRNA knockdown, in vitro proliferation and apoptosis assays, lipid accumulation assays, in vivo AML xenograft model with immune profiling by flow cytometry\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro loss-of-function with multiple defined phenotypic readouts; single lab\",\n      \"pmids\": [\"38965225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGALS1 overexpression in renal tubular cells (TCMK-1) significantly increases fibrosis and upregulates PI3K and AKT phosphorylation; nobiletin treatment reduces Lgals1 expression and inhibits PI3K/AKT phosphorylation, establishing an Lgals1/PI3K/AKT signaling axis in renal fibrosis.\",\n      \"method\": \"Lgals1 overexpression in TCMK-1 cells, western blot for PI3K/AKT phosphorylation, TGF-β-induced fibrosis model, in vivo 5/6 nephrectomy CKD mouse model\",\n      \"journal\": \"Renal Failure\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, OE with pathway readout but limited mechanistic detail on direct LGALS1-PI3K link\",\n      \"pmids\": [\"38967135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGALS1+ fibroblasts (cancer-associated fibroblasts) promote proliferation and migration of intrahepatic cholangiocarcinoma (ICC) tumor cells by upregulating CCR2, ADAM15, and β-integrin expression; silencing LGALS1 in CAFs suppresses CAF-augmented tumor cell migration and invasion in vitro and tumor formation in vivo.\",\n      \"method\": \"Single-cell RNA sequencing, siRNA/CRISPR knockout of LGALS1 in CAFs, co-culture migration/invasion assays, in vivo tumor formation model, gene expression analysis\",\n      \"journal\": \"Journal of Molecular Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — scRNA-seq combined with functional KO experiments in vitro and in vivo; single lab\",\n      \"pmids\": [\"38862197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LGALS1 knockout experiments in zebrafish xenograft models identify LGALS1 as a primary regulator of immunosuppression in glioblastoma, with LGALS1+ tumor cells driving GAM (glioblastoma-associated macrophage) polarization toward an immunosuppressive phenotype.\",\n      \"method\": \"LGALS1 knockout in patient-derived GBM stem cells, zebrafish orthotopic xenograft avatar models with real-time in vivo monitoring, single-cell RNA sequencing of GAM-GBM co-cultures, immunohistochemistry on patient tumor samples\",\n      \"journal\": \"EMBO Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including in vivo KO and single-cell sequencing; single lab\",\n      \"pmids\": [\"37791581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DUSP22 (dual-specificity phosphatase 22) directly binds LGALS1 and dephosphorylates it at Ser8 and Thr58 residues, leading to LGALS1 protein degradation; loss of LGALS1 relieves immunosuppression in the tumor microenvironment, increasing CD8+ T cell infiltration, and DUSP22 overexpression synergizes with anti-PD-1 therapy in breast cancer models.\",\n      \"method\": \"Genome-wide Sleeping Beauty transposon mutagenesis screen, mass spectrometry identification of DUSP22-LGALS1 interaction, co-immunoprecipitation validation, phosphomimetic mutant experiments to confirm Ser8/Thr58 dephosphorylation sites, flow cytometry for T cell infiltration, in vivo mouse models, bulk and single-cell RNA sequencing\",\n      \"journal\": \"Journal for Immunotherapy of Cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — identified specific phosphorylation sites by mutagenesis, validated binding by Co-IP/MS, with in vivo functional confirmation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"41611244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In pancreatic cancer, CAF-derived miR-181b-5p inhibits STING phosphorylation in tumor cells (by targeting SEC24C), which blocks YY1 nuclear translocation and de-represses LGALS1 transcription; the upregulated LGALS1 is secreted via SUSD2, suppressing CD8+ T cell function and inducing T cell apoptosis.\",\n      \"method\": \"miR-181b-5p overexpression/inhibition, STING pathway manipulation, co-culture of CAFs and pancreatic cancer cells, CD8+ T cell functional assays, LGALS1 secretion measurement, in vivo mouse tumor models\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway epistasis established by genetic manipulation with functional immune readout; single lab\",\n      \"pmids\": [\"41713839\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGALS1 (Galectin-1) is a secreted beta-galactoside-binding lectin that promotes immunosuppression (by suppressing T cell proliferation, inducing T cell apoptosis via Bcl-2/Bax modulation and IFN-γR upregulation, and polarizing tumor-associated macrophages), drives tumor cell invasion via p38 MAPK/MMP-9/EMT signaling, and supports AML cell survival and lipid metabolism; its activity is regulated post-translationally by DUSP22-mediated dephosphorylation at Ser8 and Thr58 leading to protein degradation, and transcriptionally downstream of STING signaling and by miR-22-3p targeting its 3'UTR.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper, then extract discoveries only from KEEP papers about LGALS1 (Galectin-1).\n\n**Classification:**\n- Papers about GBP (Guanylate Binding Proteins, interferon-induced GTPases): EXCLUDE (alias collision)\n- Papers about GBP (GSK-3 binding protein/FRAT in Xenopus): EXCLUDE (alias collision)\n- Papers about insect GBP (growth-blocking peptide): EXCLUDE (alias collision)\n- Papers about Leishmania/Plasmodium GBP proteins: EXCLUDE (alias collision)\n- Papers about bacterial Gbp (Fusobacterium nucleatum D-galactose binding protein): EXCLUDE (alias collision)\n- Papers about β-GBP in crustaceans: EXCLUDE (alias collision)\n- Papers about gabapentin/GBP-L drugs: EXCLUDE (alias collision)\n- Papers about genomic data (Gbp in sequencing context meaning gigabase pairs): EXCLUDE\n- Papers genuinely about LGALS1 (Galectin-1): KEEP\n\n**KEEP papers:**\n- PMID:9725202 (beta GBP = LGALS1 gene product, explicitly stated)\n- PMID:10533482 (beta GBP/LGALS1 in mammary cancer)\n- PMID:9886496 (betaGBP/LGALS1 in T cells)\n- PMID:30613962 (LGALS1 in glioma)\n- PMID:35180865 (LGALS1/NCAPG in NSCLC)\n- PMID:25687228 (LGALS1 variants)\n- PMID:30159048 (LGALS1 in oral cancer)\n- PMID:32590026 (LGALS1 in AML)\n- PMID:31428993 (LGALS1 in ccRCC)\n- PMID:37791581 (LGALS1 in GBM, zebrafish)\n- PMID:38965225 (LGALS1 in AML stem cells)\n- PMID:36224027 (miR-22-3p/LGALS1 in melanoma)\n- PMID:35872012 (LGALS1 methylation in ALS)\n- PMID:37415637 (LGALS1 in ovarian cancer)\n- PMID:38862197 (LGALS1+ fibroblasts in ICC)\n- PMID:38967135 (Lgals1/PI3K/AKT in CKD)\n- PMID:41611244 (DUSP22/LGALS1 phosphorylation)\n- PMID:41713839 (miR-181b-5p/STING/LGALS1)\n- PMID:37341175 (LGALS1 RNA-binding/AS in NSCLC)\n- PMID:8449510 (LGALS1/LGALS2 chromosomal mapping)\n- PMID:26611526 (lgals1 in loach fish - ortholog)\n- PMID:35806182 (LGALS1 genetic variants)\n- Gene2pubmed KEEP papers:\n  - PMID:8063692 (Galectins structure/function)\n  - PMID:7501023 (Galectin-1 apoptosis of T cells)\n  - PMID:10490978 (Galectin-1 apoptosis mechanism)\n  - PMID:15476813 (Galectin-1 crystal structure)\n  - PMID:15050916 (Galectin-1 tumor immune privilege)\n  - PMID:17110462 (Galectin-1 in Treg)\n  - PMID:24529377 (Galectin-1 VEGFR2 signaling)\n  - PMID:17043243 (Galectin-1 in angiogenesis)\n  - PMID:11709720 (Galectin-1 binds H-Ras)\n  - PMID:22658674 (mRNA interactome - LGALS1 identified as RBP)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Galectin-1 (LGALS1 protein) induces apoptosis of activated human T cells and T leukemia cell lines. The apoptotic effect requires expression of CD45, is decreased when N-glycan elongation is blocked by swainsonine, and is potentiated by inhibition of O-glycan elongation, demonstrating that specific glycan structures on target cells govern galectin-1-mediated cell death. Endothelial cells expressing galectin-1 could similarly induce apoptosis of bound T cells.\",\n      \"method\": \"Cell-based apoptosis assays with activated vs. resting T cells, glycosylation inhibitors (swainsonine), antibody blocking of CD45, endothelial cell co-culture\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, replicated in multiple cell types, foundational paper with >900 citations\",\n      \"pmids\": [\"7501023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Galectin-1 binding to activated T cells induces redistribution of specific surface glycoproteins (CD45, CD43, CD7) into segregated membrane microdomains. CD45 and CD3 co-localize on large apoptotic blebs with externalized phosphatidylserine, while CD7 and CD43 localize to separate patches. This receptor segregation is required for galectin-1-triggered apoptosis signaling, as it was not observed in cells resistant to galectin-1-induced death.\",\n      \"method\": \"Confocal microscopy, immunofluorescence co-localization, annexin V staining for phosphatidylserine externalization in T cell lines and primary thymocytes\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct imaging of membrane reorganization with functional correlation, multiple cell types, >270 citations\",\n      \"pmids\": [\"10490978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Beta-galactoside binding protein (betaGBP), the LGALS1 gene product, arrests activated T lymphocytes in S and G2/M phases of the cell cycle and up-regulates expression of both alpha- and beta-chains of the IFN-gamma receptor on activated T lymphoblasts, rendering them sensitive to IFN-gamma-induced apoptosis. These effects are independent of sugar binding, as saturating lactose does not block cell cycle arrest or IFN-gamma receptor up-regulation.\",\n      \"method\": \"Flow cytometry cell cycle analysis, FACS quantification of IFN-gamma receptor chains, lactose competition assay, proliferation assays with PHA-activated T cells and malignant T cell lines\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, sugar-independence established by competition assay, directly identifies LGALS1 product\",\n      \"pmids\": [\"9725202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"BetaGBP (LGALS1 product) causes S/G2 growth arrest in both normal and leukemic T cells, but selectively induces apoptosis in leukemic T cells. Apoptosis in leukemic cells correlates with decreased Bcl-2 and consequent predominance of Bax, whereas normal T cells that survive maintain Bcl-2:Bax ratio unchanged, indicating the Bcl-2/Bax balance governs differential apoptotic sensitivity.\",\n      \"method\": \"Flow cytometry cell cycle analysis, western blot for Bcl-2 and Bax protein levels in normal vs. leukemic T cells\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct comparison of normal vs. leukemic cells with molecular mechanism (Bcl-2/Bax), single lab\",\n      \"pmids\": [\"9886496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"BetaGBP (LGALS1 product) induces cell cycle block prior to G2 entry followed by progressive apoptotic death in three human mammary cancer cell lines with different oncogenic potential, estrogen receptor, and EGFR family expression status, suggesting a general mechanism not dependent on these specific markers.\",\n      \"method\": \"Flow cytometry cell cycle analysis, apoptosis assays in MCF-7, MDA-MB-231, and SK-BR-3 cell lines\",\n      \"journal\": \"European journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell lines with different molecular profiles tested, single lab\",\n      \"pmids\": [\"10533482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Galectin-1 (LGALS1) selectively binds oncogenic H-Ras(12V) but not wild-type H-Ras, K-Ras(12V), or N-Ras(13V), forming a direct protein-protein complex (molecular weight equal to sum of both proteins). Galectin-1 promotes membrane anchorage of H-Ras(12V), increases Ras-GTP and active ERK, and drives cell transformation that is blocked by dominant-negative Ras. Galectin-1 antisense RNA abolishes membrane anchorage of GFP-H-Ras(12V). Farnesylthiosalicylic acid (FTS) disrupts H-Ras(12V)-galectin-1 interactions.\",\n      \"method\": \"Co-immunoprecipitation, molecular weight analysis of complex, GFP-Ras localization by fluorescence microscopy, antisense knockdown, dominant-negative Ras rescue, ERK activation assay, cell transformation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including co-IP, localization, functional rescue, and pharmacological disruption; >327 citations\",\n      \"pmids\": [\"11709720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Crystal structure of human galectin-1 defines the ligand-binding pocket structure and carbohydrate recognition domain. Single-site mutations C2S and R111H at sites distant from the carbohydrate recognition domain alter the presentation of the loop harboring Asp123 and shift key sugar-binding residues His52 and Trp68, reducing ligand affinity through increased entropic penalty. The positions of SH-groups restrict intramolecular disulfide bridge formation but the C2S mutant displays improved stability under oxidative conditions.\",\n      \"method\": \"X-ray crystallography, isothermal titration calorimetry for thermodynamic analysis of ligand binding\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure determination plus functional validation by calorimetry; >250 citations\",\n      \"pmids\": [\"15476813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Targeted knockdown of galectin-1 (LGALS1) gene expression in tumor cells results in heightened T cell-mediated tumor rejection in vivo in syngeneic mice, identifying galectin-1 as a key mediator of tumor immune privilege. Mice that rejected Gal-1-deficient tumors subsequently resisted challenge with wild-type Gal-1-sufficient tumors, demonstrating generation of a lasting tumor-specific T cell response.\",\n      \"method\": \"Antisense RNA knockdown of Gal-1 in tumor cells, syngeneic mouse tumor challenge models, T cell functional assays, tumor re-challenge experiments\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with defined immune phenotype, re-challenge experiments, >440 citations\",\n      \"pmids\": [\"15050916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Galectin-1 is essential for tumor angiogenesis. Galectin-1 is the receptor for the angiogenesis inhibitor anginex. Knockdown of galectin-1 in cultured endothelial cells inhibits cell proliferation and migration. In zebrafish, galectin-1 knockdown impairs vascular guidance and produces dysfunctional vessels. In gal-1-null mice, tumor growth is markedly impaired due to insufficient tumor angiogenesis, and tumors no longer respond to antiangiogenesis treatment by anginex.\",\n      \"method\": \"Pulldown/receptor identification for anginex, siRNA knockdown in endothelial cells, zebrafish morpholino knockdown with vascular imaging, syngeneic tumor implantation in gal-1-null knockout mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods in vitro and in vivo including genetic null mice and zebrafish; >398 citations\",\n      \"pmids\": [\"17043243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Galectin-1 is a key effector of the suppressive function of CD4+CD25+ regulatory T cells (Tregs). Galectin-1 expression is upregulated in Tregs after activation. Blockade of galectin-1 binding significantly reduces the inhibitory effects of both human and mouse Tregs. CD4+CD25+ T cells from galectin-1-null mice show reduced regulatory activity.\",\n      \"method\": \"Gene expression analysis, antibody blockade of galectin-1 in suppression assays, Treg suppression assays using galectin-1-null mouse cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — antibody blockade plus genetic null mouse cells with functional suppression readout; >392 citations\",\n      \"pmids\": [\"17110462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Galectin-1 (Gal-1) preserves angiogenesis in tumors refractory to anti-VEGF therapy by binding complex N-glycans on VEGFR2, activating VEGF-like signaling in a glycosylation-dependent manner. Vessels in anti-VEGF-refractory tumors exhibit glycosylation patterns that facilitate Gal-1-endothelial cell interactions, while sensitive tumors display α2-6-linked sialic acid that prevents Gal-1 binding. Interrupting β1-6GlcNAc branching in ECs or silencing tumor-derived Gal-1 converts refractory tumors to anti-VEGF-sensitive tumors.\",\n      \"method\": \"Lectin binding assays, siRNA knockdown of tumor Gal-1 and endothelial glycosyltransferases, tumor implantation in Gal-1-null mice, VEGFR2 signaling readouts, glycan analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic identification of VEGFR2 as Gal-1 receptor, multiple genetic manipulations, in vivo validation, >421 citations\",\n      \"pmids\": [\"24529377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LGALS1 is identified as an mRNA-binding protein in human HeLa cells through systematic UV crosslinking-based mRNA interactome capture, revealing an unexpected RNA-binding activity for this galectin.\",\n      \"method\": \"UV crosslinking of proteins to mRNA followed by oligo(dT) capture and mass spectrometry (interactome capture)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — unbiased genome-wide method, but LGALS1 is one of >860 proteins identified without specific functional follow-up\",\n      \"pmids\": [\"22658674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LGALS1 knockdown in glioblastoma (GBM) cells remodels the immunosuppressive tumor microenvironment by downregulating M2 macrophage polarization and myeloid-derived suppressor cells (MDSCs) and inhibiting immunosuppressive cytokines, demonstrating that LGALS1 actively maintains immunosuppression in GBM.\",\n      \"method\": \"siRNA knockdown of LGALS1 in GBM cells with in vitro and in vivo assessment of immune cell composition (M2 macrophages, MDSCs) and cytokine profiling\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined immune phenotype readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"30613962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LGALS1 silencing in highly invasive oral cancer cells suppresses p38 MAPK phosphorylation, downregulates MMP-9 expression, and inhibits epithelial-mesenchymal transition (EMT) markers, while its expression drives invasion through this p38 MAPK pathway.\",\n      \"method\": \"siRNA knockdown of LGALS1, wound healing assay, transwell invasion assay, western blot for p38 MAPK phosphorylation, MMP-9, and EMT markers, in vivo lung metastasis mouse model\",\n      \"journal\": \"Therapeutic advances in medical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with pathway-level mechanistic readouts and in vivo validation, single lab\",\n      \"pmids\": [\"30159048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LGALS1 acts as a pro-survival molecule in acute myeloid leukemia (AML). In vivo, shRNA suppression of LGALS1 in OCI-AML3 xenograft-bearing mice significantly extends survival. LGALS1 suppression affects distinct transcriptional programs in p53-WT (OCI-AML3) versus p53-mutant (THP-1) AML cell lines, with the p53 pathway prominently altered in OCI-AML3 cells.\",\n      \"method\": \"shRNA knockdown in xenograft mouse model, RNASeq gene expression profiling, comparison of p53-WT vs p53-mutant cell lines\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo xenograft model with survival endpoint plus transcriptomic pathway analysis, single lab\",\n      \"pmids\": [\"32590026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NCAPG promotes NSCLC oncogenesis through upregulation of LGALS1 expression, and LGALS1 may directly interact with NCAPG. Transcriptome sequencing identified LGALS1 as a downstream mediator of NCAPG function in promoting initiation and progression of NSCLC.\",\n      \"method\": \"Transcriptome sequencing, TCGA database analysis, NCAPG knockdown in vitro and in vivo, Ncapg+/- mice with urethane-induced lung tumors, interaction studies between NCAPG and LGALS1\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — NCAPG-LGALS1 interaction suggested but not rigorously validated; LGALS1 role described as downstream without direct mechanistic proof\",\n      \"pmids\": [\"35180865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LGALS1 in glioblastoma acts as a primary regulator of immunosuppression. LGALS1 knockout experiments in zebrafish xenograft models demonstrate that LGALS1 modulates GBM-associated macrophage (GAM) polarization and attraction. Single-cell RNA sequencing of GAM-GBM co-cultures revealed LGALS1-dependent molecular heterogeneity correlated with patient survival.\",\n      \"method\": \"Single-cell RNA sequencing, LGALS1 knockout experiments in orthotopic zebrafish xenograft models, immunohistochemistry on patient tumor samples, GAM-GBM co-culture systems\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout in vivo model combined with single-cell transcriptomics and patient sample validation\",\n      \"pmids\": [\"37791581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGALS1 repression in AML cells and leukemia stem cells (LSCs) inhibits cell proliferation, enhances apoptosis, and decreases lipid accumulation in vitro. In vivo, LGALS1 repression curbs AML progression and lipid accumulation while increasing CD8+ T and NK cell counts, establishing LGALS1 as a regulator of lipid metabolism and immune evasion in LSCs.\",\n      \"method\": \"shRNA/siRNA knockdown in AML cell lines and LSCs, in vivo AML mouse model, lipid quantification assays, flow cytometry for CD8+ T and NK cells\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in vitro and in vivo with multiple defined readouts, single lab\",\n      \"pmids\": [\"38965225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGALS1+ fibroblasts activate proliferation and migration of intrahepatic cholangiocarcinoma (ICC) tumor cells by upregulating CCR2, ADAM15, and β-integrin expression. Silencing LGALS1 in cancer-associated fibroblasts (CAFs) suppresses CAF-augmented tumor cell migration and invasion in vitro and tumor formation in vivo.\",\n      \"method\": \"Single-cell RNA sequencing, siRNA knockdown of LGALS1 in CAFs, in vitro migration/invasion assays, in vivo tumor formation models\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined molecular mediators (CCR2, ADAM15, β-integrin) and in vivo validation\",\n      \"pmids\": [\"38862197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lgals1 overexpression in kidney cells (TCMK-1) significantly increases fibrosis and upregulates PI3K and AKT phosphorylation activity. LGALS1/Lgals1 is overexpressed in CKD kidney interstitium and acts upstream of the PI3K/AKT signaling pathway to drive renal fibrosis.\",\n      \"method\": \"Overexpression of Lgals1 in TCMK-1 cells, PI3K and AKT phosphorylation assays, CKD mouse model (5/6 nephrectomy), fibrosis assessment\",\n      \"journal\": \"Renal failure\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with pathway-level mechanistic readouts in vitro and in vivo CKD model\",\n      \"pmids\": [\"38967135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGALS1 functions as an RNA-binding protein that regulates alternative splicing (AS) events in NSCLC cells. LGALS1 silencing in A549 cells produces 433 upregulated and 481 downregulated AS events. LGALS1-regulated AS genes are enriched in apoptosis and ErbB signaling pathways. LGALS1 silencing alters the AS ratio of BCAP29 (decreased) and CSNKIE and MDFIC (increased), and these effects are rescued by LGALS1 overexpression.\",\n      \"method\": \"RNA sequencing after siRNA-mediated LGALS1 knockdown in A549 cells, RT-qPCR validation of AS events, LGALS1 overexpression rescue experiments\",\n      \"journal\": \"Advances in clinical and experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic transcriptomic analysis with rescue experiments confirming LGALS1-specific AS regulation\",\n      \"pmids\": [\"37341175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DUSP22 binds LGALS1 directly and dephosphorylates it at Ser8 and Thr58 residues, leading to LGALS1 protein degradation. This dephosphorylation-dependent degradation of LGALS1 alleviates LGALS1-mediated immunosuppression and increases CD8+ T-cell infiltration in the tumor microenvironment. In breast cancer, LGALS1 expression negatively correlates with both DUSP22 levels and CD8+ T-cell infiltration.\",\n      \"method\": \"AP-MS protein interaction identification, co-immunoprecipitation validation, phosphomimetic mutant experiments identifying Ser8 and Thr58 as dephosphorylation sites, flow cytometry and IHC for CD8+ T-cell infiltration, in vivo mouse tumor models, analysis of bulk and scRNA-seq data\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct identification of phosphorylation sites by mutagenesis, Co-IP validation, in vivo functional consequences, multiple orthogonal methods\",\n      \"pmids\": [\"41611244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In pancreatic cancer, CAF-derived miR-181b-5p inhibits STING phosphorylation in tumor cells, blocking YY1 nuclear translocation and de-repressing LGALS1 transcription. The upregulated LGALS1 is secreted (via SUSD2 assistance) and suppresses CD8+ T cell function and induces their apoptosis, establishing a stromal-immune axis linking STING pathway inhibition to LGALS1-mediated immunosuppression.\",\n      \"method\": \"miRNA overexpression/inhibition, STING pathway manipulation, YY1 localization assays, SUSD2 co-expression studies, CD8+ T cell functional assays, in vitro and in vivo tumor models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway epistasis established through multiple genetic manipulations with defined mechanistic steps, single lab\",\n      \"pmids\": [\"41713839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"LGALS1 and LGALS2 (encoding L-14-I and L-14-II S-lac lectins) reside in close proximity on human chromosome 22q12-q13, suggesting a cluster of genes for lactose-binding proteins.\",\n      \"method\": \"Chromosomal mapping by in situ hybridization and linkage analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct chromosomal mapping experiment\",\n      \"pmids\": [\"8449510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-22-3p directly binds to and suppresses LGALS1 mRNA (confirmed by dual luciferase reporter assay). Overexpression of miR-22-3p in melanoma cells decreases LGALS1 expression, reduces cell viability, decreases VIM and SNAI2, increases CDH1, and increases apoptosis, inhibiting EMT. Exosomes from mesenchymal stem cells loaded with miR-22-3p reproduce these effects.\",\n      \"method\": \"Dual luciferase reporter assay for miR-22-3p binding to LGALS1 3'UTR, miR-22-3p overexpression, western blot for EMT markers, cell viability assay, exosome-mediated delivery\",\n      \"journal\": \"Frontiers in bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding confirmed by luciferase assay with functional downstream validation, single lab\",\n      \"pmids\": [\"36224027\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGALS1 (Galectin-1) is a beta-galactoside-binding lectin that operates through both extracellular glycan-dependent mechanisms and intracellular protein-protein interactions: extracellularly, it induces apoptosis of activated T cells by binding specific glycoproteins (CD45, CD43, CD7) and driving their segregation into membrane microdomains in a glycan-dependent manner; it promotes tumor angiogenesis by binding complex N-glycans on VEGFR2 to activate VEGF-like signaling; and it mediates tumor immune privilege by suppressing T cell activity and serving as a key effector of regulatory T cell function; intracellularly, it selectively binds oncogenic H-Ras(12V) to stabilize its membrane anchorage and activate ERK-driven transformation, functions as an RNA-binding protein regulating alternative splicing, and is subject to phosphorylation at Ser8/Thr58 by DUSP22-mediated dephosphorylation leading to its degradation and relief of immunosuppression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LGALS1 (Galectin-1) is a β-galactoside-binding lectin that functions as a multifaceted immunomodulator and pro-tumorigenic factor, linking tumor immune evasion, cell cycle regulation, and invasion across diverse tissue contexts. LGALS1 suppresses anti-tumor immunity by inducing T cell cycle arrest and apoptosis through modulation of the Bcl-2/Bax ratio and upregulation of IFN-γ receptor expression, and by polarizing tumor-associated macrophages toward immunosuppressive phenotypes and suppressing CD8+ T cell and NK cell function [PMID:9725202, PMID:9886496, PMID:30613962, PMID:37791581, PMID:38965225]. LGALS1 promotes tumor cell invasion and metastasis via activation of p38 MAPK/MMP-9 signaling and induction of epithelial–mesenchymal transition, and in cancer-associated fibroblasts it drives tumor cell migration through upregulation of CCR2 and β-integrin [PMID:30159048, PMID:38862197]. LGALS1 protein stability is regulated by DUSP22-mediated dephosphorylation at Ser8 and Thr58, which targets LGALS1 for degradation and thereby relieves immunosuppression, while its transcription is controlled by STING/YY1 signaling and post-transcriptionally by miR-22-3p [PMID:41611244, PMID:41713839, PMID:36224027].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing the genomic context of LGALS1, chromosomal mapping placed it at 22q12-q13 in a cluster with LGALS2, indicating an evolutionary relationship among lactose-binding lectins.\",\n      \"evidence\": \"Somatic cell hybrid analysis and in situ hybridization\",\n      \"pmids\": [\"8449510\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional significance of the gene cluster was established\", \"No regulatory elements identified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"The first mechanistic link between LGALS1 and immune regulation was established: exogenous LGALS1 protein arrests T cells in S/G2M phase, upregulates IFN-γ receptor to sensitize cells to apoptosis (sugar-binding-independent), and selectively kills leukemic T cells by decreasing Bcl-2 relative to Bax.\",\n      \"evidence\": \"Flow cytometry cell cycle analysis, IFN-γR surface expression assays, Bcl-2/Bax western blots in primary T cells and leukemic T cell lines treated with recombinant protein; lactose competition controls\",\n      \"pmids\": [\"9725202\", \"9886496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which LGALS1 alters Bcl-2 expression not resolved\", \"Whether sugar-binding-independent effects operate through a specific receptor unknown\", \"In vivo relevance of T cell apoptosis induction not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"LGALS1 was positioned as a direct driver of tumor invasion and immune evasion: silencing LGALS1 in oral cancer cells abrogated p38 MAPK/MMP-9/EMT-driven invasion and lung metastasis, while in glioblastoma, LGALS1 knockdown remodeled the immunosuppressive microenvironment by reducing M2 macrophages and MDSCs.\",\n      \"evidence\": \"siRNA knockdown with Transwell invasion, wound healing, in vivo lung metastasis (oral cancer); siRNA knockdown with flow cytometry for immune populations and cytokine profiling in vitro and in vivo (GBM)\",\n      \"pmids\": [\"30159048\", \"30613962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LGALS1 binding partner activating p38 MAPK not identified\", \"Whether LGALS1 acts cell-autonomously or via secreted form in macrophage polarization not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"LGALS1 was established as a pro-survival factor in acute myeloid leukemia, with its suppression prolonging survival in xenograft models and sensitizing AML cells to BCL2 inhibition.\",\n      \"evidence\": \"shRNA knockdown in OCI-AML3 cells, in vivo xenograft survival model, RNASeq, drug sensitivity assays with ABT-737\",\n      \"pmids\": [\"32590026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking LGALS1 to BCL2 family regulation in AML not delineated\", \"Whether LGALS1 functions cell-autonomously or through immune modulation in AML survival not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Post-transcriptional regulation of LGALS1 was defined: miR-22-3p directly targets the LGALS1 3'UTR to suppress its expression, reversing EMT and promoting apoptosis in melanoma cells.\",\n      \"evidence\": \"Dual luciferase reporter assay confirming direct 3'UTR binding, miR-22-3p overexpression, western blot for EMT markers, exosome-mediated delivery\",\n      \"pmids\": [\"36224027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological abundance of miR-22-3p in tumor microenvironment not established\", \"Whether miR-22-3p regulation of LGALS1 operates in non-melanoma contexts unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"LGALS1 was validated as a primary driver of macrophage immunosuppressive polarization in glioblastoma using knockout models and single-cell transcriptomics, confirming findings from earlier knockdown studies.\",\n      \"evidence\": \"LGALS1 knockout in patient-derived GBM stem cells, zebrafish orthotopic xenograft, scRNA-seq of GAM-GBM co-cultures, patient tumor immunohistochemistry\",\n      \"pmids\": [\"37791581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor on macrophages mediating LGALS1-driven polarization not identified\", \"Whether LGALS1-dependent GAM polarization is reversible therapeutically not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"LGALS1 function was extended to leukemia stem cell maintenance and lipid metabolism: LGALS1 repression inhibited LSC proliferation, reduced lipid accumulation, and relieved CD8+ T cell and NK cell suppression in AML, while in cancer-associated fibroblasts LGALS1 promoted cholangiocarcinoma invasion via CCR2/ADAM15/β-integrin.\",\n      \"evidence\": \"shRNA knockdown with in vitro proliferation/lipid assays and in vivo AML xenograft immune profiling (AML); siRNA/CRISPR KO in CAFs with co-culture invasion assays and in vivo tumor formation (ICC)\",\n      \"pmids\": [\"38965225\", \"38862197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which LGALS1 regulates fatty acid metabolism unknown\", \"Whether LGALS1 in CAFs acts through secreted lectin or intracellular signaling not resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Post-translational control of LGALS1 stability was defined: DUSP22 dephosphorylates LGALS1 at Ser8 and Thr58, triggering its degradation and relieving immunosuppression; separately, a CAF-derived miR-181b-5p/STING/YY1 axis was shown to de-repress LGALS1 transcription, with secreted LGALS1 suppressing CD8+ T cells.\",\n      \"evidence\": \"Sleeping Beauty transposon screen, mass spectrometry, Co-IP, phosphomimetic mutants, in vivo anti-PD-1 synergy (DUSP22); miR-181b-5p manipulation, STING pathway epistasis, CD8+ T cell functional assays, in vivo mouse models (pancreatic cancer)\",\n      \"pmids\": [\"41611244\", \"41713839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase(s) responsible for Ser8/Thr58 phosphorylation not identified\", \"Structural basis of DUSP22-LGALS1 interaction unknown\", \"Whether SUSD2-mediated secretion is the predominant export pathway across tumor types not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the cell-surface receptor(s) through which secreted LGALS1 signals on T cells and macrophages, the kinase(s) that phosphorylate LGALS1 at Ser8/Thr58 to stabilize it, and the structural basis for its sugar-binding-independent immunomodulatory activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-surface receptor mediating LGALS1 immunosuppressive signaling not identified\", \"Kinase responsible for LGALS1 Ser8/Thr58 phosphorylation unknown\", \"Structural mechanism for lectin-independent activities not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 5, 12, 13]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 5, 9, 12, 13, 14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 10, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"DUSP22\",\n      \"NCAPG\",\n      \"SUSD2\",\n      \"MMP9\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Galectin-1 (LGALS1) is a β-galactoside-binding lectin that functions as a central immunomodulatory and pro-tumorigenic effector through both extracellular glycan-dependent and intracellular protein–protein interaction mechanisms. Extracellularly, it induces apoptosis of activated T cells by binding glycoproteins CD45, CD43, and CD7 and driving their segregation into distinct membrane microdomains [PMID:7501023, PMID:10490978], suppresses antitumor immunity as a key effector of regulatory T cell function [PMID:17110462], promotes tumor angiogenesis by engaging complex N-glycans on VEGFR2 to activate VEGF-like signaling [PMID:24529377], and its phosphorylation at Ser8/Thr58 is regulated by DUSP22-mediated dephosphorylation leading to its degradation and relief of immunosuppression [PMID:41611244]. Intracellularly, it selectively binds oncogenic H-Ras(12V) to stabilize its membrane anchorage and activate ERK-driven transformation [PMID:11709720], and regulates alternative splicing as an RNA-binding protein [PMID:37341175, PMID:22658674]. The crystal structure reveals a carbohydrate recognition domain in which distant mutations allosterically alter sugar-binding residue geometry and reduce ligand affinity [PMID:15476813].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Chromosomal mapping placed LGALS1 at 22q12-q13 in a cluster with LGALS2, establishing the genomic context for this lectin family member.\",\n      \"evidence\": \"In situ hybridization and linkage analysis on human chromosomes\",\n      \"pmids\": [\"8449510\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No regulatory elements characterized at this locus\", \"Functional significance of LGALS1-LGALS2 clustering unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"The first major functional role of galectin-1 was established: it induces apoptosis of activated T cells in a glycan-dependent, CD45-requiring manner, revealing it as an extracellular death signal for immune cells.\",\n      \"evidence\": \"Cell-based apoptosis assays with glycosylation inhibitors and CD45 blocking antibodies in primary T cells and T leukemia lines\",\n      \"pmids\": [\"7501023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream intracellular death signaling pathway not defined\", \"Structural basis of glycan selectivity unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Galectin-1 was shown to arrest T cells in S/G2M and upregulate IFN-γ receptor expression through a sugar-independent mechanism, demonstrating that its immunomodulatory activities extend beyond lectin-mediated apoptosis.\",\n      \"evidence\": \"Flow cytometry cell cycle analysis and FACS quantification of IFN-γ receptor with lactose competition in PHA-activated T cells\",\n      \"pmids\": [\"9725202\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the sugar-independent receptor or intracellular target unknown\", \"Relationship between cell cycle arrest and apoptosis not fully resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"The spatial mechanism of galectin-1-induced T cell death was elucidated: it triggers segregation of CD45, CD43, and CD7 into distinct membrane microdomains with phosphatidylserine externalization on apoptotic blebs, and differential Bcl-2/Bax balance governs susceptibility in leukemic versus normal T cells.\",\n      \"evidence\": \"Confocal immunofluorescence co-localization of surface glycoproteins, annexin V staining, and Bcl-2/Bax western blotting in normal and leukemic T cells\",\n      \"pmids\": [\"10490978\", \"9886496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling intermediates connecting receptor segregation to Bcl-2 downregulation undefined\", \"Whether receptor segregation is sufficient or merely correlated with death not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"An intracellular lectin-independent function was discovered: galectin-1 selectively binds oncogenic H-Ras(12V) (not WT H-Ras, K-Ras, or N-Ras), stabilizes its membrane anchorage, and activates ERK to drive transformation.\",\n      \"evidence\": \"Co-immunoprecipitation, GFP-Ras localization, antisense knockdown, dominant-negative rescue, and transformation assays\",\n      \"pmids\": [\"11709720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for H-Ras(12V) selectivity over other Ras isoforms unknown\", \"Physiological contexts where this interaction drives oncogenesis in patients not established\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The crystal structure of galectin-1 defined the carbohydrate recognition domain architecture and revealed that distant mutations allosterically shift key sugar-binding residues, while in vivo loss-of-function identified galectin-1 as a mediator of tumor immune privilege.\",\n      \"evidence\": \"X-ray crystallography with ITC thermodynamic analysis; antisense knockdown in syngeneic mouse tumor models with T cell-mediated rejection and re-challenge\",\n      \"pmids\": [\"15476813\", \"15050916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of galectin-1 in complex with full glycoprotein ligands\", \"Mechanism by which tumor galectin-1 specifically suppresses antitumor T cells versus other immune cells not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Galectin-1 was identified as essential for tumor angiogenesis (serving as the receptor for anginex) and as a critical effector of regulatory T cell suppressive function, broadening its role from direct T cell killing to vascular and Treg biology.\",\n      \"evidence\": \"Anginex pulldown/receptor identification, siRNA in endothelial cells, zebrafish morpholino, gal-1-null mouse tumor models; antibody blockade and gal-1-null Treg suppression assays\",\n      \"pmids\": [\"17043243\", \"17110462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endothelial receptor(s) mediating galectin-1 angiogenic signaling not yet identified at this point\", \"Whether Treg-derived galectin-1 acts in trans on effector T cells or in cis on Tregs not distinguished\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Unbiased mRNA interactome capture identified galectin-1 as an RNA-binding protein, suggesting a previously unrecognized intracellular function beyond lectin and Ras-binding activities.\",\n      \"evidence\": \"UV crosslinking and oligo(dT) capture followed by mass spectrometry in HeLa cells\",\n      \"pmids\": [\"22658674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No specific RNA targets or functional consequences identified at this stage\", \"RNA-binding domain not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The molecular basis of galectin-1-driven tumor angiogenesis was resolved: it binds complex N-glycans on VEGFR2 to activate VEGF-like signaling, and α2-6 sialylation blocks this interaction, explaining anti-VEGF therapy resistance.\",\n      \"evidence\": \"Lectin binding, siRNA of tumor galectin-1 and endothelial glycosyltransferases, gal-1-null mouse tumor models, VEGFR2 signaling assays\",\n      \"pmids\": [\"24529377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether galectin-1 engages additional endothelial receptors beyond VEGFR2 not excluded\", \"Therapeutic strategies to block galectin-1-VEGFR2 interaction in patients not validated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Galectin-1 was shown to drive tumor cell invasion via p38 MAPK/MMP-9/EMT signaling and to maintain immunosuppressive tumor microenvironments by promoting M2 macrophage polarization and MDSC accumulation in glioblastoma.\",\n      \"evidence\": \"siRNA knockdown with western blot for p38/MMP-9/EMT markers and in vivo metastasis models; LGALS1 knockdown in GBM cells with immune cell composition and cytokine profiling\",\n      \"pmids\": [\"30159048\", \"30613962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect effects of galectin-1 on macrophage polarization not delineated\", \"Whether p38 MAPK activation requires extracellular glycan binding or intracellular interaction unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"miR-22-3p was confirmed as a direct post-transcriptional suppressor of LGALS1 mRNA, and its delivery reverses EMT in melanoma, establishing a regulatory axis controlling galectin-1 expression.\",\n      \"evidence\": \"Dual luciferase reporter assay for miR-22-3p binding to LGALS1 3′UTR, miR-22-3p overexpression with EMT marker and apoptosis readouts\",\n      \"pmids\": [\"36224027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether miR-22-3p regulation of LGALS1 operates in non-melanoma contexts untested\", \"Other miRNAs targeting LGALS1 not systematically evaluated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Galectin-1's role as a primary immunosuppressive regulator in GBM was refined at single-cell resolution, showing it controls GBM-associated macrophage molecular heterogeneity correlated with patient survival.\",\n      \"evidence\": \"LGALS1 knockout in zebrafish orthotopic xenografts, single-cell RNA sequencing of GAM-GBM co-cultures, patient tissue immunohistochemistry\",\n      \"pmids\": [\"37791581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal versus correlative relationship between LGALS1-dependent GAM states and survival not formally tested\", \"Whether findings from zebrafish xenografts translate to mammalian immune microenvironment unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The RNA-binding function of galectin-1 was functionally validated: it regulates hundreds of alternative splicing events in NSCLC cells, with specific targets (BCAP29, CSNK1E, MDFIC) confirmed by rescue experiments, and it promotes AML progression partly through lipid metabolism regulation and PI3K/AKT-driven renal fibrosis.\",\n      \"evidence\": \"RNA-seq after LGALS1 siRNA with overexpression rescue in A549 cells; shRNA in AML xenograft models with lipid and immune readouts; Lgals1 overexpression in kidney cells with PI3K/AKT phosphorylation assays and CKD mouse model\",\n      \"pmids\": [\"37341175\", \"38965225\", \"38967135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA-binding domain of galectin-1 not mapped\", \"Whether splicing regulation is direct (RNA contact) or indirect (signaling-mediated) not resolved\", \"PI3K/AKT activation mechanism by galectin-1 not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A post-translational control mechanism was identified: DUSP22 directly dephosphorylates galectin-1 at Ser8 and Thr58, triggering its degradation and relieving immunosuppression with increased CD8+ T cell infiltration; separately, CAF-derived miR-181b-5p suppresses STING/YY1 signaling to de-repress LGALS1 transcription in pancreatic cancer.\",\n      \"evidence\": \"AP-MS, co-IP, phosphomimetic mutagenesis, in vivo mouse tumor models with flow cytometry for CD8+ T cells; miRNA manipulation with STING pathway epistasis and CD8+ T cell functional assays\",\n      \"pmids\": [\"41611244\", \"41713839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase(s) responsible for Ser8/Thr58 phosphorylation not identified\", \"Whether DUSP22-mediated degradation occurs via proteasomal or lysosomal pathway unknown\", \"Generalizability of STING-YY1-LGALS1 axis beyond pancreatic cancer untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for galectin-1's selectivity for H-Ras(12V) over other Ras isoforms, the identity and mapping of its RNA-binding domain, the kinase(s) that phosphorylate Ser8/Thr58, and whether its glycan-dependent and glycan-independent immunomodulatory activities operate through shared or distinct downstream signaling cascades.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No co-crystal structure with H-Ras(12V)\", \"RNA-binding domain unmapped\", \"Phosphorylating kinase unknown\", \"Glycan-dependent versus glycan-independent signaling convergence untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1, 6, 10]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [11, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 9, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 8, 9, 10, 22]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 7, 9, 12, 16, 17, 21, 22]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 3, 4, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 10, 13, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 8, 10, 14]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [11, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HRAS\",\n      \"VEGFR2\",\n      \"CD45\",\n      \"CD43\",\n      \"CD7\",\n      \"DUSP22\",\n      \"SUSD2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}