{"gene":"LGALS3","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1989,"finding":"Mac-2 (LGALS3) is a galactose-specific lectin that binds IgE. In vitro synthesized Mac-2 protein displayed carbohydrate- and IgE-binding properties. The protein is found in the cytosol and secreted extracellularly despite lacking a signal peptide or transmembrane domain, indicating an unconventional secretion mechanism.","method":"cDNA cloning, immunoscreening, in vitro translation, pulse-chase analysis, subcellular fractionation","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro biochemical demonstration of lectin and IgE binding, subcellular fractionation, multiple orthogonal methods in a single study replicated across subsequent literature","pmids":["2584931"],"is_preprint":false},{"year":1991,"finding":"Mac-2/CBP35 (LGALS3) forms disulfide-linked homodimers using cysteine 186 (the single cysteine residue). Dimeric CBP35 binds laminin with higher affinity than monomer in a lactosamine-dependent manner. Site-directed mutagenesis of Cys186 abolished dimerization.","method":"Non-reducing SDS-PAGE, recombinant protein expression in E. coli, laminin affinity chromatography, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis confirming the specific residue required, multiple orthogonal biochemical methods","pmids":["1917966"],"is_preprint":false},{"year":1991,"finding":"Mac-2 (LGALS3) binds two Mac-2-binding glycoproteins (M2BP-1, 98 kDa; M2BP-2, 70 kDa) via its carbohydrate-binding domain interacting with sugar moieties on the glycoproteins. Binding is inhibited by galactose or lactose, confirming lectin-mediated interaction.","method":"Immunoprecipitation, immunoaffinity chromatography with galactose/lactose elution, peptide mapping, N-terminal sequencing","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — affinity purification with specific sugar inhibition competition assay confirming carbohydrate-dependent binding mechanism","pmids":["1917996"],"is_preprint":false},{"year":1993,"finding":"The murine Mac-2 (LGALS3) gene encodes proteins that lack a functional signal peptide (confirmed by in vitro expression and translocation experiments). Most Mac-2 protein is present in the cytosol. Two alternatively spliced variants both lack functional signal peptides, supporting unconventional export.","method":"In vitro expression and translocation assays, subcellular fractionation, S1 nuclease mapping, sequence analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro translocation assay directly demonstrated absence of functional signal peptide; replicated finding from earlier subcellular fractionation data","pmids":["8509379"],"is_preprint":false},{"year":1993,"finding":"Mac-2 (LGALS3) undergoes nuclear localization in differentiated colonic epithelial cells. During neoplastic progression (adenoma and carcinoma), Mac-2 is excluded from the nucleus and localizes to the cytoplasm. Sequencing of Mac-2 cDNAs from normal mucosa and carcinoma revealed no mutations accounting for the loss of nuclear localization.","method":"Immunohistochemistry on human tissue specimens, cDNA sequencing, subcellular localization by microscopy","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct subcellular localization by IHC with sequencing analysis, but no functional mechanistic follow-up on the localization change","pmids":["7682704"],"is_preprint":false},{"year":1994,"finding":"Mac-2 (LGALS3) surface expression on thioglycollate-elicited macrophages is mediated by affinity for cell-surface carbohydrate structures, primarily alpha-galactosyl residues. Chemical cross-linking identified three Mac-2-binding glycoproteins (92, 125, and 180 kDa) containing alpha-galactosyl and polylactosamine structures on macrophage surfaces. Secretion is stimulated by calcium ionophore A23187.","method":"Chemical cross-linking, lectin binding assays, cell surface expression analysis, calcium ionophore stimulation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — chemical cross-linking identified binding partners; multiple orthogonal methods but single lab","pmids":["8308013"],"is_preprint":false},{"year":1994,"finding":"Mac-2 (LGALS3) surface expression in macrophage cell lines is regulated at the level of protein secretion: WEHI-3 cells (immature macrophages) synthesize similar amounts of Mac-2 as mature J774.2 and P388.D1 cells but fail to secrete it, preventing surface expression.","method":"Comparative analysis of macrophage cell lines, exogenous protein addition, plant lectin binding assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct cellular experiments comparing secretion and surface expression across cell lines, single lab","pmids":["8020558"],"is_preprint":false},{"year":1996,"finding":"Galectin-3 (LGALS3/Mac-2) on the cell surface binds Mac-2-binding protein (M2BP) in a specific carbohydrate-dependent manner. M2BP induces homotypic cell aggregation inhibited by lactose or anti-galectin-3 Fab' fragments, demonstrating galectin-3-mediated cell-cell adhesion.","method":"Cell binding assays with affinity-purified M2BP, homotypic cell aggregation assays with lactose inhibition and antibody blocking","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional cell adhesion assay with multiple specific inhibitors (lactose, Fab fragments), replicated across labs","pmids":["8813152"],"is_preprint":false},{"year":1997,"finding":"Galectin-3 (LGALS3) binds multiple macrophage surface glycoproteins including CD11b (integrin alpha subunit of Mac-1), LAMP-1, LAMP-2, Mac-3, and CD98 heavy chain. CD11b/CD18, CD98, and Mac-3 are identified as major surface receptors for galectin-3 on peritoneal macrophages.","method":"Galectin-3 affinity column purification from cell lysates, surface biotinylation, N-terminal sequencing, immunoprecipitation with specific antibodies","journal":"Glycoconjugate journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — affinity purification combined with surface biotinylation, sequencing, and confirmatory immunoprecipitation; multiple orthogonal methods","pmids":["9111144"],"is_preprint":false},{"year":1998,"finding":"The human LGALS3 gene is composed of six exons and five introns spanning ~17 kb, with the carbohydrate recognition sequence in exon V and the proline-glycine-alanine-tyrosine (PGAY) repeat motif in exon III. Galectin-3 functions as a pre-mRNA splicing factor. The promoter is serum-responsive with activation regions at -513 to -339 nt and -339 to -229 nt.","method":"Southern blot, primer extension, RNase protection assay, luciferase reporter transfection in HeLa cells and fibroblasts","journal":"Archives of biochemistry and biophysics","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — gene structure determination combined with functional promoter assays, multiple methods in single study","pmids":["9439577"],"is_preprint":false},{"year":1999,"finding":"Mac-2-binding protein (M2BP) forms linear and ring-shaped oligomers; rings predominate as decamers of ~14 nm segments each comprising two 92 kDa M2BP monomers. The N-terminal domain (domain 1/SRCR domain) is monomeric and inactive in cell attachment, while domains 2-4 retain cell-adhesive potential and form ring-like structures.","method":"Scanning transmission electron microscopy, transmission electron microscopy, analytical ultracentrifugation, cell attachment assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct structural characterization by EM combined with functional domain dissection and ultracentrifugation","pmids":["10452890"],"is_preprint":false},{"year":2002,"finding":"M2BP domain 2 (BTB/POZ domain) is the dimerization domain of M2BP. Domains 3-4 contain binding sites for galectin-3, nidogen, and collagens V and VI. Cell adhesive activity requires concerted binding and/or multivalent ring interactions, as isolated fragments showed no cell adhesive activity.","method":"Recombinant domain expression in HEK293 cells, analytical ultracentrifugation, CD spectroscopy, trypsin susceptibility, electron microscopy, solid phase binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — recombinant domain reconstitution with multiple structural and functional assays in single study","pmids":["11867635"],"is_preprint":false},{"year":2005,"finding":"Galig (LGALS3 internal gene) encodes a mitochondrial protein named mitogaligin that promotes cytochrome c release from mitochondria, causing cell death. Mitochondrial targeting relies on an internal sequence that is required and sufficient for cytochrome c release. Bcl-xL (but not Bcl-2) co-transfection significantly reduced galig-induced cytochrome c release.","method":"Cell transfection, cytochrome c release assay, isolated mitochondria incubation with mitogaligin peptides, co-transfection with Bcl-xL/Bcl-2, structure-activity relationship studies","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct in vitro reconstitution with isolated mitochondria plus cellular validation, structure-activity analysis identifying required sequence","pmids":["15561101"],"is_preprint":false},{"year":2008,"finding":"Galectin-3/MAC-2 (LGALS3) activates PI3K-dependent phagocytosis of degenerated myelin by microglia through Ras (predominantly K-Ras). Galectin-3 co-immunoprecipitates with Ras and the co-immunoprecipitate levels increase during phagocytosis. FTS (which inhibits galectin-3-dependent Ras activation) inhibited phagocytosis and reduced K-Ras-GTP levels and PI3K activity.","method":"Co-immunoprecipitation, pharmacological inhibition with FTS, K-Ras-GTP level measurement, PI3K activity assay, phagocytosis assay","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP combined with functional pharmacological rescue and biochemical activity assays, multiple orthogonal methods","pmids":["18615637"],"is_preprint":false},{"year":2008,"finding":"Endosialin (Tem1), a tumor stroma glycoprotein, is a binding partner of Mac-2 BP/90K. A C-terminal fragment of Mac-2 BP containing binding sites for galectin-3 and collagens mediates endosialin binding. The interaction results in a repulsive outcome: Mac-2 BP-expressing tumor cells show reduced adhesion to endosialin-expressing fibroblasts.","method":"Biochemical pulldown, domain mapping, loss-of-function adhesion experiments","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — biochemical binding assay with domain mapping and functional cell adhesion experiments, single lab","pmids":["18490383"],"is_preprint":false},{"year":2014,"finding":"Galectin-3 (LGALS3) interacts with BARD1 (the main partner of BRCA1) and participates in the DNA damage response. Knockdown of galectin-3 delays DDR response activation and decreases G2/M cell cycle checkpoint arrest associated with the homologous recombination pathway. TAP-MS identified the galectin-3 protein interaction network.","method":"Co-IP/TAP-MS, siRNA knockdown, DNA damage response assays, cell cycle analysis","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — TAP-MS interaction identification combined with functional KD analysis, single lab with two orthogonal methods","pmids":["24755837"],"is_preprint":false},{"year":2016,"finding":"KLF3 (Krüppel-like factor 3) directly represses galectin-3 (LGALS3) transcription by binding CACCC box elements in the Lgals3 promoter. CtBP co-factor is required for optimal KLF3-mediated silencing. Lgals3 is broadly upregulated in KLF3-deficient mouse tissues.","method":"KLF3 knockout mice, chromatin immunoprecipitation (ChIP), EMSA, luciferase reporter assays, cellular molecular analyses","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP demonstrating direct promoter occupancy, EMSA for direct binding, functional knockout phenotype, multiple orthogonal methods in single study","pmids":["27226561"],"is_preprint":false},{"year":2018,"finding":"Lgals3 deficiency in mice increases osteoblastogenesis with little-to-no effect on osteoclastogenesis, resulting in enhanced cortical bone expansion and protection from age-related trabecular bone loss. Galectin-3 is identified as a negative regulator of bone formation.","method":"Lgals3-knockout mice, histomorphometry, ex vivo primary cell differentiation assays for osteoblastogenesis and osteoclastogenesis","journal":"Bone research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with histomorphometry and cell differentiation assays, single lab, defined cellular phenotype","pmids":["30886760"],"is_preprint":false},{"year":2019,"finding":"Galectin-3 (LGALS3/MAC-2) controls microglial morphology and phagocytosis by regulating cytoskeletal organization. Knockdown of galectin-3 transforms microglia from amoeboid to branched morphology, rearranges actin filaments, and inactivates cofilin. Galectin-3 activates phagocytosis by: (1) advancing cofilin activation to drive filopodia/lamellipodia extension/engulfment, and (2) promoting actin/myosin contraction through K-Ras-GTP/PI3K signaling to drive retraction/internalization.","method":"Galectin-3 shRNA knockdown in primary microglia, morphological analysis, actin filament staining, cofilin activation assay, phagocytosis assay","journal":"Frontiers in cellular neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — specific shRNA KD with multiple cellular phenotype readouts (morphology, cytoskeleton, phagocytosis), mechanistic pathway defined","pmids":["30930748"],"is_preprint":false},{"year":2021,"finding":"LGALS3 (galectin-3) mediates unconventional secretion of SNCA/α-synuclein following vesicular/lysosomal membrane damage in human midbrain dopamine neurons. SNCA release through this pathway is dependent on TRIM16 and ATG16L1, indicating that galectin-3 routes SNCA to an autophagic secretory pathway triggered by lysosomal membrane damage.","method":"Human midbrain dopamine neuronal culture model, gain/loss-of-function experiments, vesicular damage assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mechanistic cell biology with specific pathway component knockdowns, single lab, human neuronal model","pmids":["34612142"],"is_preprint":false},{"year":2022,"finding":"SREBP1 positively regulates LGALS3 expression in smooth muscle cells under cholesterol loading, forming a feedforward circuit. KLF15 acts as a negative regulator at a discrete promoter site. BRD2 co-immunoprecipitates with SREBP1's transcription-active domain and occupies both the SREBP1 promoter and the Lgals3 promoter. BET inhibition blocks cholesterol-stimulated SREBP1/LGALS3 production.","method":"ChIP-qPCR, EMSA, co-immunoprecipitation, siRNA silencing, BET inhibitor treatment in mouse/rat/human SMCs","journal":"Molecular therapy. Nucleic acids","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP, EMSA, and Co-IP used together with functional inhibitor validation in multiple species, multiple orthogonal methods in single study","pmids":["35694209"],"is_preprint":false},{"year":2023,"finding":"Periplocin prevents LGALS3 Lys210 ubiquitination-mediated proteasomal degradation by directly binding LGALS3, thereby upregulating it and inducing excessive lysophagy in colorectal cancer cells, exacerbating lysosomal damage and causing cell death. Inhibition of LGALS3-mediated lysophagy attenuates periplocin-induced effects.","method":"In vitro and in vivo CRC cell assays, ubiquitination assay, proteasome inhibition, LGALS3 knockdown/overexpression","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay with specific lysine site identification and functional rescue assays, single lab","pmids":["37471054"],"is_preprint":false},{"year":2023,"finding":"Mesenchymal ovarian cancer cells communicate via LGALS3 to LAG3 receptor on CD8+ T cells, promoting T cell exhaustion in the tumor microenvironment. High LGALS3 expression is associated with EMT in vivo and validated in in vitro EMT models.","method":"Single-cell and spatial transcriptomic analysis, in vitro EMT models, intercellular communication analysis","journal":"NPJ systems biology and applications","confidence":"Low","confidence_rationale":"Tier 3-4 / Weak — primarily transcriptomic/computational with in vitro EMT validation but no direct receptor binding or functional blocking experiments reported in abstract","pmids":["38086828"],"is_preprint":false},{"year":2024,"finding":"HDAC7 promotes LGALS3 secretion via a HDAC7-H3K27ac-SOX8/JUN-LGALS3 axis. HDAC7 inhibits SOX8 via H3K27 deacetylation; reduced SOX8 facilitates JUN-driven LGALS3 transcription. Secreted LGALS3 binds ITGB1 on GBM cancer stem cells (autocrine) and macrophages (paracrine) to promote mesenchymal transition and M2 polarization.","method":"Mass spectrometry, RNA immunoprecipitation (RIP), co-immunoprecipitation, HDAC7 gain/loss-of-function in vitro and in vivo, H3K27 deacetylation assays","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RIP, and mass spectrometry with in vitro/in vivo functional validation, single lab with multiple orthogonal methods","pmids":["39629136"],"is_preprint":false},{"year":2024,"finding":"Lgals3 interacts directly with pyruvate kinase M2 (PKM2) and promotes PKM2 expression by modulating E3 ligase Trim21, preventing PKM2 ubiquitination. This increases glycolysis and lactate production, leading to H3K18 lactylation that drives FGFR4 transcription and activation, promoting calcium oxalate crystal deposition and kidney injury. Lgals3 knockout reduces CaOx deposition and renal fibrosis in vivo.","method":"Co-IP, Lgals3 knockout mice, ubiquitination assay, histone lactylation analysis, FGFR4 expression analysis, in vitro and in vivo CaOx models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying direct PKM2 interaction, ubiquitination assay, and KO mouse model, single lab with multiple methods","pmids":["39903812"],"is_preprint":false},{"year":2025,"finding":"USP15 deubiquitinates and stabilizes LGALS3 in hepatocellular carcinoma cells, increasing LGALS3 stability and activating AKT/mTOR signaling to promote HCC cell stemness, proliferation, and lenvatinib resistance. Mettl3 N6-methyladenosine (m6A) modification stabilizes USP15 mRNA, upstream of this pathway.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, MeRIP-qPCR, siRNA knockdown, cell growth/colony/spheroid assays, xenograft mouse model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay identifying deubiquitination mechanism, validated in vivo with xenograft, single lab","pmids":["39794359"],"is_preprint":false},{"year":2020,"finding":"RNF219-mediated α-catenin degradation activates a YAP1/β-catenin complex that epigenetically upregulates LGALS3 promoter activity, increasing LGALS3 secretion. HCC-secreted LGALS3 promotes osteoclast fusion and podosome formation, forming a bone pre-metastatic niche for HCC bone metastasis.","method":"Gain/loss-of-function in HCC cells, promoter epigenetic modification analysis, osteoclast differentiation assays, in vivo xenograft bone metastasis models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional in vivo and in vitro experiments identifying upstream regulatory axis, single lab","pmids":["33643786"],"is_preprint":false},{"year":2024,"finding":"LGALS3 induces EndoMT (endothelial-to-mesenchymal transition) in endothelial cells by activating PI3K/AKT signaling in silica-induced pulmonary fibrosis. LGALS3 interference blocked EndoMT by inhibiting PI3K/AKT activity, and PI3K inhibitor LY294002 alleviated silica-induced pulmonary fibrosis in vivo.","method":"SiO2-induced EndoMT cell model, siRNA knockdown of LGALS3, PI3K inhibitor treatment, mouse silicosis model","journal":"Toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene KD with pathway inhibitor validation in both in vitro and in vivo models, single lab","pmids":["39353502"],"is_preprint":false},{"year":2020,"finding":"M2BPGi (glycosylated form of Mac-2 BP) binds to galectin-3 (LGALS3) to induce membranous galectin-3 expression in HCC cells and activates mTOR signaling, promoting tumor growth. M2BP mRNA is detected in cirrhotic liver stromal cells while M2BPGi and galectin-3 proteins co-localize in HCC cells.","method":"Transcriptome analysis, galectin-3/mTOR signaling assays, in vitro M2BPGi treatment of HCC cells, in vivo xenograft mouse model, co-localization immunohistochemistry","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional signaling assay with in vivo validation and co-localization data, single lab","pmids":["32624579"],"is_preprint":false},{"year":1995,"finding":"Mac-2-binding protein (M2BP) binds to immobilized CD14 in an LPS-dependent manner. M2BP alone did not enable cellular responses to LPS, nor block plasma-enabled LPS responses, but M2BP slowed LPS neutralization mediated by plasma lipoproteins.","method":"Affinity chromatography over immobilized CD14 with/without LPS, purified M2BP functional assays with CD14-bearing cells","journal":"Journal of inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical binding demonstrated with affinity chromatography and functional cellular assays, single lab","pmids":["7583357"],"is_preprint":false}],"current_model":"LGALS3 (Mac-2/galectin-3) is a beta-galactoside-binding lectin that lacks a conventional signal peptide and is secreted by an unconventional pathway from the cytosol; it functions extracellularly as an oligomeric (predominantly decameric ring) cell adhesion and opsonization molecule binding glycoprotein ligands (including Mac-2 BP/90K, laminin, CD11b/CD18, LAMP-1/2, and others) through its carbohydrate recognition domain, while intracellularly it activates K-Ras/PI3K signaling to drive cytoskeletal remodeling and phagocytosis in microglia/macrophages, participates in DNA damage response via BARD1 interaction, controls lysosomal membrane damage sensing and autophagic secretion of alpha-synuclein, and its transcription is directly repressed by KLF3 (via CtBP co-factor) and activated by SREBP1 (via BRD2) in response to cholesterol loading."},"narrative":{"mechanistic_narrative":"LGALS3 (Mac-2/galectin-3) is a beta-galactoside-binding lectin that functions in cell adhesion, macrophage/microglial phagocytosis, intracellular signaling, and lysosomal damage responses [PMID:2584931, PMID:18615637, PMID:34612142]. It is synthesized without a functional signal peptide and resides predominantly in the cytosol, yet is exported by an unconventional, calcium-stimulated secretion route that controls its surface display and adhesive activity [PMID:2584931, PMID:8509379, PMID:8308013, PMID:8020558]. Extracellularly it engages glycoprotein ligands through its carbohydrate recognition domain: it binds Mac-2-binding protein (M2BP/90K), laminin, and macrophage surface receptors including CD11b/CD18, LAMP-1/2, Mac-3, and CD98, with interactions inhibited by galactose or lactose, and it mediates carbohydrate-dependent homotypic cell adhesion [PMID:1917966, PMID:1917996, PMID:8813152, PMID:9111144]. Oligomerization underlies these adhesive functions, with a single cysteine (Cys186) supporting disulfide-linked dimers that bind laminin more avidly than monomer [PMID:1917966]. Intracellularly, galectin-3 co-immunoprecipitates with Ras and activates predominantly K-Ras/PI3K signaling to drive phagocytosis, controlling microglial morphology by advancing cofilin activation and promoting actin/myosin contraction [PMID:18615637, PMID:30930748]. It also routes alpha-synuclein to an autophagic secretory pathway after lysosomal membrane damage via TRIM16 and ATG16L1, and participates in the DNA damage response through interaction with BARD1 [PMID:34612142, PMID:24755837]. LGALS3 transcription is directly repressed by KLF3 (with CtBP) and activated by SREBP1 (with BRD2) under cholesterol loading, and its protein stability is governed by ubiquitination at Lys210 and deubiquitination by USP15 [PMID:27226561, PMID:35694209, PMID:37471054, PMID:39794359].","teleology":[{"year":1989,"claim":"Established the founding identity of Mac-2/LGALS3 as a galactose-specific lectin that binds IgE and, despite lacking a signal peptide, reaches the extracellular space — defining both its ligand class and the unconventional secretion puzzle.","evidence":"cDNA cloning, in vitro translation, subcellular fractionation and pulse-chase","pmids":["2584931"],"confidence":"High","gaps":["Secretion machinery not identified","Physiological IgE-binding role unresolved"]},{"year":1991,"claim":"Resolved the structural basis of avidity by showing Cys186-dependent disulfide dimerization enhances laminin binding, linking oligomeric state to adhesive function.","evidence":"Non-reducing SDS-PAGE, recombinant expression, laminin affinity chromatography, Cys186 mutagenesis","pmids":["1917966","1917996"],"confidence":"High","gaps":["Higher-order oligomerization in vivo not defined","Relative roles of dimer vs monomer in tissue contexts unknown"]},{"year":1993,"claim":"Confirmed that LGALS3 splice variants lack functional signal peptides and that most protein is cytosolic, cementing unconventional export as the route to its extracellular roles, and noted nuclear exclusion during colon neoplasia.","evidence":"In vitro translocation assays, subcellular fractionation, S1 nuclease mapping, IHC on human tissue","pmids":["8509379","7682704"],"confidence":"High","gaps":["Mechanism of nuclear vs cytoplasmic partitioning unresolved","Functional consequence of nuclear exclusion not tested"]},{"year":1994,"claim":"Showed surface display is controlled at the level of secretion and dependent on affinity for cell-surface carbohydrate (alpha-galactosyl/polylactosamine), explaining why protein synthesis alone does not predict surface lectin function.","evidence":"Chemical cross-linking, lectin binding assays, calcium ionophore stimulation, comparison across macrophage cell lines","pmids":["8308013","8020558"],"confidence":"Medium","gaps":["Trigger for physiological secretion in vivo unknown","Single-lab cell-line comparisons"]},{"year":1996,"claim":"Demonstrated galectin-3 mediates carbohydrate-dependent homotypic cell-cell adhesion via M2BP, providing direct functional proof of its lectin-bridging adhesion role.","evidence":"Cell binding and homotypic aggregation assays with lactose inhibition and anti-galectin-3 Fab blocking","pmids":["8813152"],"confidence":"High","gaps":["In vivo adhesion contribution not quantified"]},{"year":1997,"claim":"Identified the macrophage surface receptor repertoire (CD11b/CD18, CD98, Mac-3, LAMP-1/2), mapping the glycoprotein ligands through which galectin-3 acts at the cell surface.","evidence":"Galectin-3 affinity purification, surface biotinylation, N-terminal sequencing, confirmatory immunoprecipitation","pmids":["9111144"],"confidence":"High","gaps":["Functional consequence of each receptor engagement not dissected"]},{"year":2002,"claim":"Defined the architecture of the M2BP ligand — BTB/POZ-mediated dimerization and decameric ring oligomers — and localized galectin-3, nidogen, and collagen binding sites, clarifying the multivalent platform galectin-3 engages.","evidence":"EM, analytical ultracentrifugation, CD spectroscopy, recombinant domain dissection, solid-phase binding","pmids":["10452890","11867635"],"confidence":"High","gaps":["Stoichiometry of galectin-3:M2BP complex in vivo unknown"]},{"year":2008,"claim":"Revealed an intracellular signaling function: galectin-3 binds Ras and activates K-Ras/PI3K to drive microglial phagocytosis of myelin, extending its role beyond extracellular adhesion.","evidence":"Co-IP, FTS pharmacological inhibition, K-Ras-GTP and PI3K activity assays, phagocytosis assay","pmids":["18615637"],"confidence":"High","gaps":["Mechanism of cytosolic galectin-3 reaching Ras unresolved","Direct vs indirect Ras binding not distinguished"]},{"year":2014,"claim":"Connected galectin-3 to the DNA damage response through a BARD1 interaction influencing G2/M checkpoint and homologous recombination, indicating a nuclear function.","evidence":"TAP-MS interaction mapping, siRNA knockdown, DDR and cell cycle assays","pmids":["24755837"],"confidence":"Medium","gaps":["Direct BARD1 binding not biochemically reconstituted","Single lab; mechanism of checkpoint regulation undefined"]},{"year":2016,"claim":"Identified direct transcriptional repression of LGALS3 by KLF3 via CACCC-box binding with CtBP, providing the first defined upstream transcriptional control.","evidence":"KLF3-knockout mice, ChIP, EMSA, luciferase reporter assays","pmids":["27226561"],"confidence":"High","gaps":["Cell-type specificity of repression not mapped"]},{"year":2019,"claim":"Mechanistically linked galectin-3 to cytoskeletal control of microglial phagocytosis, showing it advances cofilin activation and drives actin/myosin contraction through K-Ras/PI3K.","evidence":"shRNA knockdown in primary microglia, morphology and actin imaging, cofilin activation and phagocytosis assays","pmids":["30930748"],"confidence":"High","gaps":["Direct molecular link between galectin-3 and cofilin pathway not defined"]},{"year":2021,"claim":"Defined a lysosomal-damage-sensing role in which galectin-3 routes alpha-synuclein to autophagic secretion via TRIM16 and ATG16L1, implicating it in unconventional protein release after membrane injury.","evidence":"Human midbrain dopamine neuron cultures, gain/loss-of-function, vesicular damage assays","pmids":["34612142"],"confidence":"Medium","gaps":["Direct galectin-3/TRIM16/ATG16L1 binding hierarchy not resolved","Single lab"]},{"year":2022,"claim":"Established a cholesterol-responsive SREBP1/BRD2 feedforward circuit activating LGALS3, with KLF15 as a counter-repressor, defining metabolic transcriptional regulation.","evidence":"ChIP-qPCR, EMSA, Co-IP, siRNA, BET inhibition in mouse/rat/human smooth muscle cells","pmids":["35694209"],"confidence":"High","gaps":["Direct vs indirect BRD2 recruitment to Lgals3 promoter not fully separated"]},{"year":2023,"claim":"Showed LGALS3 protein levels are set post-translationally by ubiquitination at Lys210 and proteasomal degradation, with stabilization driving lysophagy and cell death in colorectal cancer.","evidence":"Ubiquitination assay, proteasome inhibition, periplocin binding, knockdown/overexpression in CRC cells in vitro and in vivo","pmids":["37471054"],"confidence":"Medium","gaps":["E3 ligase acting on Lys210 not identified","Single lab"]},{"year":2025,"claim":"Identified USP15 as a deubiquitinase that stabilizes LGALS3 to activate AKT/mTOR, defining the deubiquitination arm of its stability control and a stemness/drug-resistance output.","evidence":"Co-IP, mass spectrometry, ubiquitination assay, MeRIP-qPCR, knockdown, spheroid and xenograft assays in HCC","pmids":["39794359"],"confidence":"Medium","gaps":["Direct USP15-LGALS3 binding interface not mapped","Single lab"]},{"year":null,"claim":"How cytosolic galectin-3 is selected for unconventional secretion, and how its monomer/dimer/oligomer state is coordinated with its distinct intracellular (Ras, BARD1, lysophagy) versus extracellular (adhesion, receptor engagement) functions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Secretion machinery and selectivity unknown","Switch between intracellular signaling and extracellular adhesion roles undefined","Structural basis of in vivo oligomerization not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[13,18]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,5,7]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,18]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[19,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[16,20]}],"complexes":[],"partners":["LGALS3BP","CD11B/ITGAM","LAMP1","LAMP2","BARD1","KRAS","PKM2","USP15"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P17931","full_name":"Galectin-3","aliases":["35 kDa lectin","Carbohydrate-binding protein 35","CBP 35","Galactose-specific lectin 3","Galactoside-binding protein","GALBP","IgE-binding protein","L-31","Laminin-binding protein","Lectin L-29","Mac-2 antigen"],"length_aa":250,"mass_kda":26.2,"function":"Galactose-specific lectin which binds IgE. May mediate with the alpha-3, beta-1 integrin the stimulation by CSPG4 of endothelial cells migration. Together with DMBT1, required for terminal differentiation of columnar epithelial cells during early embryogenesis (By similarity). In the nucleus: acts as a pre-mRNA splicing factor. Involved in acute inflammatory responses including neutrophil activation and adhesion, chemoattraction of monocytes macrophages, opsonization of apoptotic neutrophils, and activation of mast cells. 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In vitro synthesized Mac-2 protein displayed carbohydrate- and IgE-binding properties. The protein is found in the cytosol and secreted extracellularly despite lacking a signal peptide or transmembrane domain, indicating an unconventional secretion mechanism.\",\n      \"method\": \"cDNA cloning, immunoscreening, in vitro translation, pulse-chase analysis, subcellular fractionation\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro biochemical demonstration of lectin and IgE binding, subcellular fractionation, multiple orthogonal methods in a single study replicated across subsequent literature\",\n      \"pmids\": [\"2584931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Mac-2/CBP35 (LGALS3) forms disulfide-linked homodimers using cysteine 186 (the single cysteine residue). Dimeric CBP35 binds laminin with higher affinity than monomer in a lactosamine-dependent manner. Site-directed mutagenesis of Cys186 abolished dimerization.\",\n      \"method\": \"Non-reducing SDS-PAGE, recombinant protein expression in E. coli, laminin affinity chromatography, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis confirming the specific residue required, multiple orthogonal biochemical methods\",\n      \"pmids\": [\"1917966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Mac-2 (LGALS3) binds two Mac-2-binding glycoproteins (M2BP-1, 98 kDa; M2BP-2, 70 kDa) via its carbohydrate-binding domain interacting with sugar moieties on the glycoproteins. Binding is inhibited by galactose or lactose, confirming lectin-mediated interaction.\",\n      \"method\": \"Immunoprecipitation, immunoaffinity chromatography with galactose/lactose elution, peptide mapping, N-terminal sequencing\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — affinity purification with specific sugar inhibition competition assay confirming carbohydrate-dependent binding mechanism\",\n      \"pmids\": [\"1917996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The murine Mac-2 (LGALS3) gene encodes proteins that lack a functional signal peptide (confirmed by in vitro expression and translocation experiments). Most Mac-2 protein is present in the cytosol. Two alternatively spliced variants both lack functional signal peptides, supporting unconventional export.\",\n      \"method\": \"In vitro expression and translocation assays, subcellular fractionation, S1 nuclease mapping, sequence analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro translocation assay directly demonstrated absence of functional signal peptide; replicated finding from earlier subcellular fractionation data\",\n      \"pmids\": [\"8509379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Mac-2 (LGALS3) undergoes nuclear localization in differentiated colonic epithelial cells. During neoplastic progression (adenoma and carcinoma), Mac-2 is excluded from the nucleus and localizes to the cytoplasm. Sequencing of Mac-2 cDNAs from normal mucosa and carcinoma revealed no mutations accounting for the loss of nuclear localization.\",\n      \"method\": \"Immunohistochemistry on human tissue specimens, cDNA sequencing, subcellular localization by microscopy\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct subcellular localization by IHC with sequencing analysis, but no functional mechanistic follow-up on the localization change\",\n      \"pmids\": [\"7682704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Mac-2 (LGALS3) surface expression on thioglycollate-elicited macrophages is mediated by affinity for cell-surface carbohydrate structures, primarily alpha-galactosyl residues. Chemical cross-linking identified three Mac-2-binding glycoproteins (92, 125, and 180 kDa) containing alpha-galactosyl and polylactosamine structures on macrophage surfaces. Secretion is stimulated by calcium ionophore A23187.\",\n      \"method\": \"Chemical cross-linking, lectin binding assays, cell surface expression analysis, calcium ionophore stimulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — chemical cross-linking identified binding partners; multiple orthogonal methods but single lab\",\n      \"pmids\": [\"8308013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Mac-2 (LGALS3) surface expression in macrophage cell lines is regulated at the level of protein secretion: WEHI-3 cells (immature macrophages) synthesize similar amounts of Mac-2 as mature J774.2 and P388.D1 cells but fail to secrete it, preventing surface expression.\",\n      \"method\": \"Comparative analysis of macrophage cell lines, exogenous protein addition, plant lectin binding assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct cellular experiments comparing secretion and surface expression across cell lines, single lab\",\n      \"pmids\": [\"8020558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Galectin-3 (LGALS3/Mac-2) on the cell surface binds Mac-2-binding protein (M2BP) in a specific carbohydrate-dependent manner. M2BP induces homotypic cell aggregation inhibited by lactose or anti-galectin-3 Fab' fragments, demonstrating galectin-3-mediated cell-cell adhesion.\",\n      \"method\": \"Cell binding assays with affinity-purified M2BP, homotypic cell aggregation assays with lactose inhibition and antibody blocking\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional cell adhesion assay with multiple specific inhibitors (lactose, Fab fragments), replicated across labs\",\n      \"pmids\": [\"8813152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Galectin-3 (LGALS3) binds multiple macrophage surface glycoproteins including CD11b (integrin alpha subunit of Mac-1), LAMP-1, LAMP-2, Mac-3, and CD98 heavy chain. CD11b/CD18, CD98, and Mac-3 are identified as major surface receptors for galectin-3 on peritoneal macrophages.\",\n      \"method\": \"Galectin-3 affinity column purification from cell lysates, surface biotinylation, N-terminal sequencing, immunoprecipitation with specific antibodies\",\n      \"journal\": \"Glycoconjugate journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification combined with surface biotinylation, sequencing, and confirmatory immunoprecipitation; multiple orthogonal methods\",\n      \"pmids\": [\"9111144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The human LGALS3 gene is composed of six exons and five introns spanning ~17 kb, with the carbohydrate recognition sequence in exon V and the proline-glycine-alanine-tyrosine (PGAY) repeat motif in exon III. Galectin-3 functions as a pre-mRNA splicing factor. The promoter is serum-responsive with activation regions at -513 to -339 nt and -339 to -229 nt.\",\n      \"method\": \"Southern blot, primer extension, RNase protection assay, luciferase reporter transfection in HeLa cells and fibroblasts\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — gene structure determination combined with functional promoter assays, multiple methods in single study\",\n      \"pmids\": [\"9439577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Mac-2-binding protein (M2BP) forms linear and ring-shaped oligomers; rings predominate as decamers of ~14 nm segments each comprising two 92 kDa M2BP monomers. The N-terminal domain (domain 1/SRCR domain) is monomeric and inactive in cell attachment, while domains 2-4 retain cell-adhesive potential and form ring-like structures.\",\n      \"method\": \"Scanning transmission electron microscopy, transmission electron microscopy, analytical ultracentrifugation, cell attachment assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct structural characterization by EM combined with functional domain dissection and ultracentrifugation\",\n      \"pmids\": [\"10452890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"M2BP domain 2 (BTB/POZ domain) is the dimerization domain of M2BP. Domains 3-4 contain binding sites for galectin-3, nidogen, and collagens V and VI. Cell adhesive activity requires concerted binding and/or multivalent ring interactions, as isolated fragments showed no cell adhesive activity.\",\n      \"method\": \"Recombinant domain expression in HEK293 cells, analytical ultracentrifugation, CD spectroscopy, trypsin susceptibility, electron microscopy, solid phase binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — recombinant domain reconstitution with multiple structural and functional assays in single study\",\n      \"pmids\": [\"11867635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Galig (LGALS3 internal gene) encodes a mitochondrial protein named mitogaligin that promotes cytochrome c release from mitochondria, causing cell death. Mitochondrial targeting relies on an internal sequence that is required and sufficient for cytochrome c release. Bcl-xL (but not Bcl-2) co-transfection significantly reduced galig-induced cytochrome c release.\",\n      \"method\": \"Cell transfection, cytochrome c release assay, isolated mitochondria incubation with mitogaligin peptides, co-transfection with Bcl-xL/Bcl-2, structure-activity relationship studies\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct in vitro reconstitution with isolated mitochondria plus cellular validation, structure-activity analysis identifying required sequence\",\n      \"pmids\": [\"15561101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Galectin-3/MAC-2 (LGALS3) activates PI3K-dependent phagocytosis of degenerated myelin by microglia through Ras (predominantly K-Ras). Galectin-3 co-immunoprecipitates with Ras and the co-immunoprecipitate levels increase during phagocytosis. FTS (which inhibits galectin-3-dependent Ras activation) inhibited phagocytosis and reduced K-Ras-GTP levels and PI3K activity.\",\n      \"method\": \"Co-immunoprecipitation, pharmacological inhibition with FTS, K-Ras-GTP level measurement, PI3K activity assay, phagocytosis assay\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP combined with functional pharmacological rescue and biochemical activity assays, multiple orthogonal methods\",\n      \"pmids\": [\"18615637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Endosialin (Tem1), a tumor stroma glycoprotein, is a binding partner of Mac-2 BP/90K. A C-terminal fragment of Mac-2 BP containing binding sites for galectin-3 and collagens mediates endosialin binding. The interaction results in a repulsive outcome: Mac-2 BP-expressing tumor cells show reduced adhesion to endosialin-expressing fibroblasts.\",\n      \"method\": \"Biochemical pulldown, domain mapping, loss-of-function adhesion experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — biochemical binding assay with domain mapping and functional cell adhesion experiments, single lab\",\n      \"pmids\": [\"18490383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Galectin-3 (LGALS3) interacts with BARD1 (the main partner of BRCA1) and participates in the DNA damage response. Knockdown of galectin-3 delays DDR response activation and decreases G2/M cell cycle checkpoint arrest associated with the homologous recombination pathway. TAP-MS identified the galectin-3 protein interaction network.\",\n      \"method\": \"Co-IP/TAP-MS, siRNA knockdown, DNA damage response assays, cell cycle analysis\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — TAP-MS interaction identification combined with functional KD analysis, single lab with two orthogonal methods\",\n      \"pmids\": [\"24755837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KLF3 (Krüppel-like factor 3) directly represses galectin-3 (LGALS3) transcription by binding CACCC box elements in the Lgals3 promoter. CtBP co-factor is required for optimal KLF3-mediated silencing. Lgals3 is broadly upregulated in KLF3-deficient mouse tissues.\",\n      \"method\": \"KLF3 knockout mice, chromatin immunoprecipitation (ChIP), EMSA, luciferase reporter assays, cellular molecular analyses\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP demonstrating direct promoter occupancy, EMSA for direct binding, functional knockout phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"27226561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Lgals3 deficiency in mice increases osteoblastogenesis with little-to-no effect on osteoclastogenesis, resulting in enhanced cortical bone expansion and protection from age-related trabecular bone loss. Galectin-3 is identified as a negative regulator of bone formation.\",\n      \"method\": \"Lgals3-knockout mice, histomorphometry, ex vivo primary cell differentiation assays for osteoblastogenesis and osteoclastogenesis\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with histomorphometry and cell differentiation assays, single lab, defined cellular phenotype\",\n      \"pmids\": [\"30886760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Galectin-3 (LGALS3/MAC-2) controls microglial morphology and phagocytosis by regulating cytoskeletal organization. Knockdown of galectin-3 transforms microglia from amoeboid to branched morphology, rearranges actin filaments, and inactivates cofilin. Galectin-3 activates phagocytosis by: (1) advancing cofilin activation to drive filopodia/lamellipodia extension/engulfment, and (2) promoting actin/myosin contraction through K-Ras-GTP/PI3K signaling to drive retraction/internalization.\",\n      \"method\": \"Galectin-3 shRNA knockdown in primary microglia, morphological analysis, actin filament staining, cofilin activation assay, phagocytosis assay\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific shRNA KD with multiple cellular phenotype readouts (morphology, cytoskeleton, phagocytosis), mechanistic pathway defined\",\n      \"pmids\": [\"30930748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LGALS3 (galectin-3) mediates unconventional secretion of SNCA/α-synuclein following vesicular/lysosomal membrane damage in human midbrain dopamine neurons. SNCA release through this pathway is dependent on TRIM16 and ATG16L1, indicating that galectin-3 routes SNCA to an autophagic secretory pathway triggered by lysosomal membrane damage.\",\n      \"method\": \"Human midbrain dopamine neuronal culture model, gain/loss-of-function experiments, vesicular damage assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mechanistic cell biology with specific pathway component knockdowns, single lab, human neuronal model\",\n      \"pmids\": [\"34612142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SREBP1 positively regulates LGALS3 expression in smooth muscle cells under cholesterol loading, forming a feedforward circuit. KLF15 acts as a negative regulator at a discrete promoter site. BRD2 co-immunoprecipitates with SREBP1's transcription-active domain and occupies both the SREBP1 promoter and the Lgals3 promoter. BET inhibition blocks cholesterol-stimulated SREBP1/LGALS3 production.\",\n      \"method\": \"ChIP-qPCR, EMSA, co-immunoprecipitation, siRNA silencing, BET inhibitor treatment in mouse/rat/human SMCs\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP, EMSA, and Co-IP used together with functional inhibitor validation in multiple species, multiple orthogonal methods in single study\",\n      \"pmids\": [\"35694209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Periplocin prevents LGALS3 Lys210 ubiquitination-mediated proteasomal degradation by directly binding LGALS3, thereby upregulating it and inducing excessive lysophagy in colorectal cancer cells, exacerbating lysosomal damage and causing cell death. Inhibition of LGALS3-mediated lysophagy attenuates periplocin-induced effects.\",\n      \"method\": \"In vitro and in vivo CRC cell assays, ubiquitination assay, proteasome inhibition, LGALS3 knockdown/overexpression\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay with specific lysine site identification and functional rescue assays, single lab\",\n      \"pmids\": [\"37471054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mesenchymal ovarian cancer cells communicate via LGALS3 to LAG3 receptor on CD8+ T cells, promoting T cell exhaustion in the tumor microenvironment. High LGALS3 expression is associated with EMT in vivo and validated in in vitro EMT models.\",\n      \"method\": \"Single-cell and spatial transcriptomic analysis, in vitro EMT models, intercellular communication analysis\",\n      \"journal\": \"NPJ systems biology and applications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3-4 / Weak — primarily transcriptomic/computational with in vitro EMT validation but no direct receptor binding or functional blocking experiments reported in abstract\",\n      \"pmids\": [\"38086828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC7 promotes LGALS3 secretion via a HDAC7-H3K27ac-SOX8/JUN-LGALS3 axis. HDAC7 inhibits SOX8 via H3K27 deacetylation; reduced SOX8 facilitates JUN-driven LGALS3 transcription. Secreted LGALS3 binds ITGB1 on GBM cancer stem cells (autocrine) and macrophages (paracrine) to promote mesenchymal transition and M2 polarization.\",\n      \"method\": \"Mass spectrometry, RNA immunoprecipitation (RIP), co-immunoprecipitation, HDAC7 gain/loss-of-function in vitro and in vivo, H3K27 deacetylation assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RIP, and mass spectrometry with in vitro/in vivo functional validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39629136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lgals3 interacts directly with pyruvate kinase M2 (PKM2) and promotes PKM2 expression by modulating E3 ligase Trim21, preventing PKM2 ubiquitination. This increases glycolysis and lactate production, leading to H3K18 lactylation that drives FGFR4 transcription and activation, promoting calcium oxalate crystal deposition and kidney injury. Lgals3 knockout reduces CaOx deposition and renal fibrosis in vivo.\",\n      \"method\": \"Co-IP, Lgals3 knockout mice, ubiquitination assay, histone lactylation analysis, FGFR4 expression analysis, in vitro and in vivo CaOx models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying direct PKM2 interaction, ubiquitination assay, and KO mouse model, single lab with multiple methods\",\n      \"pmids\": [\"39903812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP15 deubiquitinates and stabilizes LGALS3 in hepatocellular carcinoma cells, increasing LGALS3 stability and activating AKT/mTOR signaling to promote HCC cell stemness, proliferation, and lenvatinib resistance. Mettl3 N6-methyladenosine (m6A) modification stabilizes USP15 mRNA, upstream of this pathway.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, MeRIP-qPCR, siRNA knockdown, cell growth/colony/spheroid assays, xenograft mouse model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay identifying deubiquitination mechanism, validated in vivo with xenograft, single lab\",\n      \"pmids\": [\"39794359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RNF219-mediated α-catenin degradation activates a YAP1/β-catenin complex that epigenetically upregulates LGALS3 promoter activity, increasing LGALS3 secretion. HCC-secreted LGALS3 promotes osteoclast fusion and podosome formation, forming a bone pre-metastatic niche for HCC bone metastasis.\",\n      \"method\": \"Gain/loss-of-function in HCC cells, promoter epigenetic modification analysis, osteoclast differentiation assays, in vivo xenograft bone metastasis models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional in vivo and in vitro experiments identifying upstream regulatory axis, single lab\",\n      \"pmids\": [\"33643786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGALS3 induces EndoMT (endothelial-to-mesenchymal transition) in endothelial cells by activating PI3K/AKT signaling in silica-induced pulmonary fibrosis. LGALS3 interference blocked EndoMT by inhibiting PI3K/AKT activity, and PI3K inhibitor LY294002 alleviated silica-induced pulmonary fibrosis in vivo.\",\n      \"method\": \"SiO2-induced EndoMT cell model, siRNA knockdown of LGALS3, PI3K inhibitor treatment, mouse silicosis model\",\n      \"journal\": \"Toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene KD with pathway inhibitor validation in both in vitro and in vivo models, single lab\",\n      \"pmids\": [\"39353502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"M2BPGi (glycosylated form of Mac-2 BP) binds to galectin-3 (LGALS3) to induce membranous galectin-3 expression in HCC cells and activates mTOR signaling, promoting tumor growth. M2BP mRNA is detected in cirrhotic liver stromal cells while M2BPGi and galectin-3 proteins co-localize in HCC cells.\",\n      \"method\": \"Transcriptome analysis, galectin-3/mTOR signaling assays, in vitro M2BPGi treatment of HCC cells, in vivo xenograft mouse model, co-localization immunohistochemistry\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional signaling assay with in vivo validation and co-localization data, single lab\",\n      \"pmids\": [\"32624579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Mac-2-binding protein (M2BP) binds to immobilized CD14 in an LPS-dependent manner. M2BP alone did not enable cellular responses to LPS, nor block plasma-enabled LPS responses, but M2BP slowed LPS neutralization mediated by plasma lipoproteins.\",\n      \"method\": \"Affinity chromatography over immobilized CD14 with/without LPS, purified M2BP functional assays with CD14-bearing cells\",\n      \"journal\": \"Journal of inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical binding demonstrated with affinity chromatography and functional cellular assays, single lab\",\n      \"pmids\": [\"7583357\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGALS3 (Mac-2/galectin-3) is a beta-galactoside-binding lectin that lacks a conventional signal peptide and is secreted by an unconventional pathway from the cytosol; it functions extracellularly as an oligomeric (predominantly decameric ring) cell adhesion and opsonization molecule binding glycoprotein ligands (including Mac-2 BP/90K, laminin, CD11b/CD18, LAMP-1/2, and others) through its carbohydrate recognition domain, while intracellularly it activates K-Ras/PI3K signaling to drive cytoskeletal remodeling and phagocytosis in microglia/macrophages, participates in DNA damage response via BARD1 interaction, controls lysosomal membrane damage sensing and autophagic secretion of alpha-synuclein, and its transcription is directly repressed by KLF3 (via CtBP co-factor) and activated by SREBP1 (via BRD2) in response to cholesterol loading.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LGALS3 (Mac-2/galectin-3) is a beta-galactoside-binding lectin that functions in cell adhesion, macrophage/microglial phagocytosis, intracellular signaling, and lysosomal damage responses [#0, #13, #19]. It is synthesized without a functional signal peptide and resides predominantly in the cytosol, yet is exported by an unconventional, calcium-stimulated secretion route that controls its surface display and adhesive activity [#0, #3, #5, #6]. Extracellularly it engages glycoprotein ligands through its carbohydrate recognition domain: it binds Mac-2-binding protein (M2BP/90K), laminin, and macrophage surface receptors including CD11b/CD18, LAMP-1/2, Mac-3, and CD98, with interactions inhibited by galactose or lactose, and it mediates carbohydrate-dependent homotypic cell adhesion [#1, #2, #7, #8]. Oligomerization underlies these adhesive functions, with a single cysteine (Cys186) supporting disulfide-linked dimers that bind laminin more avidly than monomer [#1]. Intracellularly, galectin-3 co-immunoprecipitates with Ras and activates predominantly K-Ras/PI3K signaling to drive phagocytosis, controlling microglial morphology by advancing cofilin activation and promoting actin/myosin contraction [#13, #18]. It also routes alpha-synuclein to an autophagic secretory pathway after lysosomal membrane damage via TRIM16 and ATG16L1, and participates in the DNA damage response through interaction with BARD1 [#19, #15]. LGALS3 transcription is directly repressed by KLF3 (with CtBP) and activated by SREBP1 (with BRD2) under cholesterol loading, and its protein stability is governed by ubiquitination at Lys210 and deubiquitination by USP15 [#16, #20, #21, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Established the founding identity of Mac-2/LGALS3 as a galactose-specific lectin that binds IgE and, despite lacking a signal peptide, reaches the extracellular space — defining both its ligand class and the unconventional secretion puzzle.\",\n      \"evidence\": \"cDNA cloning, in vitro translation, subcellular fractionation and pulse-chase\",\n      \"pmids\": [\"2584931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Secretion machinery not identified\", \"Physiological IgE-binding role unresolved\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Resolved the structural basis of avidity by showing Cys186-dependent disulfide dimerization enhances laminin binding, linking oligomeric state to adhesive function.\",\n      \"evidence\": \"Non-reducing SDS-PAGE, recombinant expression, laminin affinity chromatography, Cys186 mutagenesis\",\n      \"pmids\": [\"1917966\", \"1917996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Higher-order oligomerization in vivo not defined\", \"Relative roles of dimer vs monomer in tissue contexts unknown\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Confirmed that LGALS3 splice variants lack functional signal peptides and that most protein is cytosolic, cementing unconventional export as the route to its extracellular roles, and noted nuclear exclusion during colon neoplasia.\",\n      \"evidence\": \"In vitro translocation assays, subcellular fractionation, S1 nuclease mapping, IHC on human tissue\",\n      \"pmids\": [\"8509379\", \"7682704\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of nuclear vs cytoplasmic partitioning unresolved\", \"Functional consequence of nuclear exclusion not tested\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Showed surface display is controlled at the level of secretion and dependent on affinity for cell-surface carbohydrate (alpha-galactosyl/polylactosamine), explaining why protein synthesis alone does not predict surface lectin function.\",\n      \"evidence\": \"Chemical cross-linking, lectin binding assays, calcium ionophore stimulation, comparison across macrophage cell lines\",\n      \"pmids\": [\"8308013\", \"8020558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trigger for physiological secretion in vivo unknown\", \"Single-lab cell-line comparisons\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrated galectin-3 mediates carbohydrate-dependent homotypic cell-cell adhesion via M2BP, providing direct functional proof of its lectin-bridging adhesion role.\",\n      \"evidence\": \"Cell binding and homotypic aggregation assays with lactose inhibition and anti-galectin-3 Fab blocking\",\n      \"pmids\": [\"8813152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo adhesion contribution not quantified\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identified the macrophage surface receptor repertoire (CD11b/CD18, CD98, Mac-3, LAMP-1/2), mapping the glycoprotein ligands through which galectin-3 acts at the cell surface.\",\n      \"evidence\": \"Galectin-3 affinity purification, surface biotinylation, N-terminal sequencing, confirmatory immunoprecipitation\",\n      \"pmids\": [\"9111144\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of each receptor engagement not dissected\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the architecture of the M2BP ligand — BTB/POZ-mediated dimerization and decameric ring oligomers — and localized galectin-3, nidogen, and collagen binding sites, clarifying the multivalent platform galectin-3 engages.\",\n      \"evidence\": \"EM, analytical ultracentrifugation, CD spectroscopy, recombinant domain dissection, solid-phase binding\",\n      \"pmids\": [\"10452890\", \"11867635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of galectin-3:M2BP complex in vivo unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed an intracellular signaling function: galectin-3 binds Ras and activates K-Ras/PI3K to drive microglial phagocytosis of myelin, extending its role beyond extracellular adhesion.\",\n      \"evidence\": \"Co-IP, FTS pharmacological inhibition, K-Ras-GTP and PI3K activity assays, phagocytosis assay\",\n      \"pmids\": [\"18615637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of cytosolic galectin-3 reaching Ras unresolved\", \"Direct vs indirect Ras binding not distinguished\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected galectin-3 to the DNA damage response through a BARD1 interaction influencing G2/M checkpoint and homologous recombination, indicating a nuclear function.\",\n      \"evidence\": \"TAP-MS interaction mapping, siRNA knockdown, DDR and cell cycle assays\",\n      \"pmids\": [\"24755837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct BARD1 binding not biochemically reconstituted\", \"Single lab; mechanism of checkpoint regulation undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified direct transcriptional repression of LGALS3 by KLF3 via CACCC-box binding with CtBP, providing the first defined upstream transcriptional control.\",\n      \"evidence\": \"KLF3-knockout mice, ChIP, EMSA, luciferase reporter assays\",\n      \"pmids\": [\"27226561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type specificity of repression not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mechanistically linked galectin-3 to cytoskeletal control of microglial phagocytosis, showing it advances cofilin activation and drives actin/myosin contraction through K-Ras/PI3K.\",\n      \"evidence\": \"shRNA knockdown in primary microglia, morphology and actin imaging, cofilin activation and phagocytosis assays\",\n      \"pmids\": [\"30930748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between galectin-3 and cofilin pathway not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a lysosomal-damage-sensing role in which galectin-3 routes alpha-synuclein to autophagic secretion via TRIM16 and ATG16L1, implicating it in unconventional protein release after membrane injury.\",\n      \"evidence\": \"Human midbrain dopamine neuron cultures, gain/loss-of-function, vesicular damage assays\",\n      \"pmids\": [\"34612142\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct galectin-3/TRIM16/ATG16L1 binding hierarchy not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a cholesterol-responsive SREBP1/BRD2 feedforward circuit activating LGALS3, with KLF15 as a counter-repressor, defining metabolic transcriptional regulation.\",\n      \"evidence\": \"ChIP-qPCR, EMSA, Co-IP, siRNA, BET inhibition in mouse/rat/human smooth muscle cells\",\n      \"pmids\": [\"35694209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect BRD2 recruitment to Lgals3 promoter not fully separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed LGALS3 protein levels are set post-translationally by ubiquitination at Lys210 and proteasomal degradation, with stabilization driving lysophagy and cell death in colorectal cancer.\",\n      \"evidence\": \"Ubiquitination assay, proteasome inhibition, periplocin binding, knockdown/overexpression in CRC cells in vitro and in vivo\",\n      \"pmids\": [\"37471054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase acting on Lys210 not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified USP15 as a deubiquitinase that stabilizes LGALS3 to activate AKT/mTOR, defining the deubiquitination arm of its stability control and a stemness/drug-resistance output.\",\n      \"evidence\": \"Co-IP, mass spectrometry, ubiquitination assay, MeRIP-qPCR, knockdown, spheroid and xenograft assays in HCC\",\n      \"pmids\": [\"39794359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct USP15-LGALS3 binding interface not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How cytosolic galectin-3 is selected for unconventional secretion, and how its monomer/dimer/oligomer state is coordinated with its distinct intracellular (Ras, BARD1, lysophagy) versus extracellular (adhesion, receptor engagement) functions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Secretion machinery and selectivity unknown\", \"Switch between intracellular signaling and extracellular adhesion roles undefined\", \"Structural basis of in vivo oligomerization not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0030246\", \"supporting_discovery_ids\": [0, 2, 7, 8]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [13, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 18]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [19, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [16, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LGALS3BP\", \"CD11b/ITGAM\", \"LAMP1\", \"LAMP2\", \"BARD1\", \"KRAS\", \"PKM2\", \"USP15\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}