{"gene":"LGALS7","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1995,"finding":"Human galectin-7 (LGALS7) was cloned from a keratinocyte cDNA library and shown to encode a 14-kDa beta-galactoside-binding protein (IEF 17) specifically expressed in stratified squamous epithelium. The protein was partially secreted to the medium despite lacking a classical signal peptide, localized to basal keratinocytes and areas of cell-to-cell contact, and the gene was mapped to chromosome 19.","method":"cDNA cloning, two-dimensional gel electrophoresis, immunoblotting, immunofluorescence, lactose-binding assay, chromosomal mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (cloning, 2D-PAGE, lectin-binding assay, immunolocalization) in a single foundational study","pmids":["7534301"],"is_preprint":false},{"year":1995,"finding":"Galectin-7 is a 14-kDa S-lectin specifically expressed in keratinocytes at all stages of epidermal differentiation (basal and suprabasal layers). Its expression is moderately repressed by retinoic acid, consistent with a metaplasiogenic rather than a simple differentiation-stage effect. A GST fusion protein confirmed lactose-binding properties.","method":"cDNA cloning, differential hybridization, in situ hybridization, GST fusion protein lectin assay, retinoic acid treatment","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical lectin-binding confirmation plus multiple expression methods, replicated across species","pmids":["7729568"],"is_preprint":false},{"year":1997,"finding":"Galectin-7 (designated PIG1, p53-induced gene 1) was identified as a transcriptional target of p53 in colorectal carcinoma cells, placing it downstream of p53 in a pathway involving redox-related gene induction preceding apoptosis.","method":"p53-inducible expression system, transcriptional profiling (serial analysis of gene expression/differential display), pharmacological and biochemical validation","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 — systematic p53-inducible screen with functional validation, but galectin-7 is one of many identified targets","pmids":["9305847"],"is_preprint":false},{"year":1998,"finding":"Crystal structure of human galectin-7 was determined in free form and bound to galactose, galactosamine, lactose, and N-acetyl-lactosamine at high resolution. The structure revealed a fold similar to prototype galectins-1 and -2 but with greater similarity to Gal-10; carbohydrate-binding residues are conserved but a shortened loop alters the binding pocket. Galectin-7 crystallizes as a dimer with a packing arrangement distinct from galectins-1 and -2, with implications for carbohydrate recognition.","method":"X-ray crystallography with multiple ligands","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure determination in free and multiple ligand-bound forms","pmids":["9760227"],"is_preprint":false},{"year":1998,"finding":"Galectin-7 expression is a marker of all subtypes of stratified epithelia (interfollicular epidermis, outer root sheath, esophagus, oral epithelia, cornea, thymic Hassall's corpuscles) but is absent from simple and transitional epithelia, hair matrix, sebaceous glands, and carcinoma cell lines, establishing its specific distribution and loss in malignancy.","method":"In situ hybridization, immunolabeling of human/rat/mouse tissues, rat and mouse cDNA cloning","journal":"Differentiation; research in biological diversity","confidence":"High","confidence_rationale":"Tier 2 — systematic multi-tissue, multi-species characterization with consistent findings","pmids":["9697310"],"is_preprint":false},{"year":1999,"finding":"Galectin-7 mRNA and protein are rapidly upregulated after UVB irradiation of epidermal keratinocytes, in parallel with p53 stabilization. In reconstructed skin and human skin ex vivo, galectin-7 overexpression is associated with sunburn/apoptotic keratinocytes. Transfection of a galectin-7 expression vector significantly increased TUNEL-positive keratinocytes, demonstrating a direct pro-apoptotic role in UV-induced apoptosis.","method":"UVB irradiation, immunofluorescence, immunoblotting, TUNEL assay, galectin-7 expression vector transfection, reconstructed skin model, human skin ex vivo","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function transfection with TUNEL readout plus ex vivo tissue model, replicated across systems","pmids":["10500176"],"is_preprint":false},{"year":2001,"finding":"Galectin-7 functions as an intracellular pro-apoptotic protein, acting upstream of JNK activation and mitochondrial cytochrome c release. Ectopic expression in HeLa and DLD-1 cells enhanced susceptibility to apoptosis from mechanistically distinct stimuli. Apoptosis potentiation was associated with enhanced caspase-3 activity, PARP cleavage, accelerated cytochrome c release, and up-regulated JNK activity. The pro-apoptotic effect was blocked by pan-caspase inhibitor zVAD-fmk and was not attributable to extracellular lectin activity, as galectin-7 localizes to nuclei and cytoplasm. DNA microarray analysis revealed up-regulation of redox-related genes (monoamine oxidase B, ryanodine receptor 2, glutathione S-transferase Mu 3) in galectin-7-expressing cells.","method":"Stable transfection (HeLa, DLD-1), apoptosis assays with multiple stimuli, caspase-3 activity assay, PARP cleavage, cytochrome c release, JNK activity assay, caspase inhibitor rescue, immunofluorescence localization, DNA microarray","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods across two cell lines, pathway placement upstream of JNK and cytochrome c, pharmacological rescue","pmids":["11706006"],"is_preprint":false},{"year":2003,"finding":"Extracellular galectin-7 binds the GM1 ganglioside sugar chain on the surface of neuroblastoma cells (SK-N-MC), acting as a lectin to reduce cell growth without classical apoptosis features. This effect was blocked by galectin-3, mechanistically resembling galectin-1's growth-suppressive activity despite structural differences. The protein exists as a homodimer capable of crosslinking cell-surface glycoconjugates.","method":"Solid-phase binding assay, cell proliferation assay, competition assay with galectin-3, serum-supplemented culture, neuroblastoma cell lines","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — solid-phase binding plus cell assay with competition, single lab","pmids":["13679866"],"is_preprint":false},{"year":2010,"finding":"Overexpression of galectin-7 in breast cancer cells drastically increased their metastatic capacity to lungs and bones in two preclinical mouse models. This established a functional role for galectin-7 in promoting cancer metastasis in vivo, in contrast to its tumor-suppressive role in epithelial homeostasis.","method":"Stable overexpression in breast cancer cell lines, orthotopic and systemic mouse models, quantification of pulmonary metastases and osteolytic lesions, immunohistochemistry of human breast tissue","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — in vivo gain-of-function with two mouse models and quantitative metastasis readout","pmids":["20382700"],"is_preprint":false},{"year":2018,"finding":"siRNA-mediated knockdown of galectin-7 in bronchial epithelial cells (BEAS-2B) abrogated TGF-β1-induced apoptosis, decreased Bax expression, increased Bcl-2, and reduced caspase-3 cleavage and PARP cleavage. Gal-7 knockdown also inhibited TGF-β1-induced JNK phosphorylation. Rescue with the JNK activator anisomycin reversed the anti-apoptotic effect of Gal-7 silencing, placing galectin-7 upstream of JNK in TGF-β1-induced apoptosis in airway epithelial cells.","method":"siRNA knockdown, flow cytometry (apoptosis), western blotting (Bcl-2, Bax, caspase-3, PARP, p-JNK), anisomycin rescue experiment","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined pathway placement and pharmacological rescue, single lab","pmids":["30594507"],"is_preprint":false},{"year":2021,"finding":"Galectin-7 (Gal-7) physically interacts with 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) as identified by yeast two-hybrid screening and confirmed by in vitro beta-galactosidase assay, Biacore surface plasmon resonance, and co-immunoprecipitation. The interaction site on HMGCS1 was mapped to phenylalanine 26. Exogenous Gal-7 upregulates HMGCS1 expression in keratinocytes, and LGALS7 siRNA knockdown reduces HMGCS1 and cholesterol levels. HMGCS1-overexpressing cells induce Gal-7 expression in a positive feedback loop. Gal-7-mediated cholesterol elevation was blocked by wild-type but not F26-mutated HMGCS1 peptide, linking the Gal-7/HMGCS1 interaction to cellular cholesterol accumulation.","method":"Yeast two-hybrid, in vitro beta-galactosidase assay, Biacore SPR, co-immunoprecipitation, LGALS7 siRNA knockdown, HMGCS1 overexpression, cholesterol measurement, site-directed mutagenesis (F26 mutation)","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1-2 — interaction confirmed by multiple orthogonal methods including SPR and mutagenesis mapping of interaction site","pmids":["34454908"],"is_preprint":false},{"year":2020,"finding":"NMR spectroscopy demonstrated that galectin-7 interacts with glycans on the receptor-binding domain of the SARS-CoV-2 spike protein. Complementary experiments from both the glycoprotein and lectin perspectives identified specific interacting epitopes, and 3D models of the interacting complexes were proposed.","method":"NMR spectroscopy with 15N-labeled galectin-7 and 13C-labeled RBD glycans, binding epitope mapping","journal":"Angewandte Chemie (International ed. in English)","confidence":"Medium","confidence_rationale":"Tier 1 — NMR structural interaction data, but functional consequences not established for galectin-7 specifically","pmids":["32915505"],"is_preprint":false},{"year":2024,"finding":"In gastric cancer AGS cells, ANGPTL4 overexpression upregulates LGALS7 expression, and LGALS7 acts as a downstream mediator of ANGPTL4's anticancer phenotype. LGALS7 regulates the Hedgehog signaling pathway, and co-immunoprecipitation confirmed protein-level interactions in this context. LGALS7 was shown to influence proliferation, migration, apoptosis evasion, angiogenesis, and lymphangiogenesis downstream of ANGPTL4.","method":"RNA-seq, PCR, western blotting, co-immunoprecipitation, cell line overexpression/knockdown (SNU5, MKN7, AGS), functional assays (EdU, MTT, flow cytometry, wound healing, transwell, tube formation), nude mouse xenograft","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway placement via RNA-seq and co-IP with functional in vitro and in vivo validation, single lab","pmids":["39369030"],"is_preprint":false}],"current_model":"LGALS7 encodes galectin-7, a 14-kDa homodimeric beta-galactoside-binding lectin specifically expressed in stratified epithelia, which functions intracellularly as a pro-apoptotic protein acting upstream of JNK activation and mitochondrial cytochrome c release (established by gain- and loss-of-function experiments), interacts with HMGCS1 at phenylalanine 26 to promote cholesterol accumulation in keratinocytes, binds GM1 ganglioside on neuroblastoma cell surfaces to suppress proliferation, and structurally engages carbohydrates through a conserved binding pocket defined by X-ray crystallography; it is transcriptionally induced by p53 and UVB, and its overexpression promotes breast cancer metastasis in vivo while its downstream signaling involves the Hedgehog pathway in gastric cancer contexts."},"narrative":{"teleology":[{"year":1995,"claim":"Identification of galectin-7 as a keratinocyte-specific β-galactoside-binding lectin established its tissue restriction and non-classical secretion, defining the gene's identity and expression domain.","evidence":"cDNA cloning from keratinocyte library, 2D-PAGE, lactose-binding assay, immunolocalization, and chromosomal mapping across two independent studies","pmids":["7534301","7729568"],"confidence":"High","gaps":["No functional role established beyond lectin activity","Mechanism of non-classical secretion not defined","Epithelial-specific transcriptional regulation not characterized"]},{"year":1997,"claim":"Identification of galectin-7 (PIG1) as a p53 transcriptional target linked it to the tumor suppressor network and suggested a role in apoptosis-related gene programs.","evidence":"p53-inducible expression system in colorectal carcinoma cells with serial analysis of gene expression","pmids":["9305847"],"confidence":"Medium","gaps":["Galectin-7 was one of many p53-induced genes; its specific contribution to p53-mediated apoptosis was not isolated","Direct p53 binding to the LGALS7 promoter was not demonstrated"]},{"year":1998,"claim":"Crystal structure determination of galectin-7 in free and ligand-bound forms defined the carbohydrate-binding pocket and revealed a distinctive dimer interface, providing the structural basis for its lectin activity.","evidence":"X-ray crystallography with galactose, galactosamine, lactose, and N-acetyllactosamine co-crystals","pmids":["9760227"],"confidence":"High","gaps":["Structure-function relationship for intracellular (non-lectin) roles not addressed","Dimer interface contribution to biological activity not tested by mutagenesis"]},{"year":1999,"claim":"Demonstration that UVB-induced galectin-7 upregulation directly promotes keratinocyte apoptosis established its pro-apoptotic function in an epithelial damage context, converging with its p53 regulation.","evidence":"UVB irradiation of keratinocytes, galectin-7 overexpression vector transfection with TUNEL quantification, reconstructed skin and human skin ex vivo models","pmids":["10500176"],"confidence":"High","gaps":["Downstream apoptotic pathway mediators not identified","Whether lectin activity is required for apoptosis induction was not tested"]},{"year":2001,"claim":"Mechanistic dissection placed galectin-7's pro-apoptotic activity upstream of JNK activation and mitochondrial cytochrome c release, establishing it as an intracellular apoptosis amplifier independent of its extracellular lectin function.","evidence":"Stable transfection in HeLa and DLD-1 cells, caspase-3/PARP/cytochrome c/JNK assays, zVAD-fmk rescue, nuclear/cytoplasmic immunolocalization, DNA microarray","pmids":["11706006"],"confidence":"High","gaps":["Direct molecular target linking galectin-7 to JNK activation not identified","Contribution of upregulated redox genes to apoptosis not functionally validated"]},{"year":2003,"claim":"Identification of GM1 ganglioside as an extracellular binding partner revealed a second, lectin-dependent mechanism by which galectin-7 suppresses cell growth via glycoconjugate crosslinking.","evidence":"Solid-phase binding assay for GM1, cell proliferation assay in neuroblastoma cells, competition with galectin-3","pmids":["13679866"],"confidence":"Medium","gaps":["Downstream signaling from GM1 crosslinking not characterized","Relevance to epithelial biology versus neuroblastoma-specific effect not resolved"]},{"year":2010,"claim":"In vivo demonstration that galectin-7 overexpression promotes breast cancer metastasis revealed a context-dependent oncogenic function, contrasting with its tumor-suppressive apoptotic role in normal epithelia.","evidence":"Stable overexpression in breast cancer lines, orthotopic and systemic mouse models with quantified lung and bone metastases","pmids":["20382700"],"confidence":"High","gaps":["Molecular mechanism underlying metastasis promotion not defined","Whether lectin activity or intracellular functions drive metastasis not distinguished"]},{"year":2018,"claim":"Loss-of-function validation confirmed galectin-7 is required for TGF-β1-induced apoptosis in airway epithelial cells via JNK, independently replicating the JNK-cytochrome c pathway placement in a non-cancer epithelial system.","evidence":"siRNA knockdown in BEAS-2B cells, western blot for Bax/Bcl-2/caspase-3/PARP/p-JNK, anisomycin rescue of JNK activity","pmids":["30594507"],"confidence":"Medium","gaps":["Single cell line from a single laboratory","Direct physical interaction between galectin-7 and JNK pathway components not shown"]},{"year":2021,"claim":"Identification of HMGCS1 as a direct physical interactor at phenylalanine 26 revealed a non-lectin intracellular function of galectin-7 in cholesterol metabolism, expanding its roles beyond apoptosis.","evidence":"Yeast two-hybrid, SPR, co-IP, F26 mutagenesis, siRNA knockdown and overexpression with cholesterol quantification in keratinocytes","pmids":["34454908"],"confidence":"High","gaps":["Whether the HMGCS1 interaction operates through galectin-7's carbohydrate-binding site or an independent surface not resolved","Physiological consequence of altered cholesterol in keratinocytes not defined in vivo"]},{"year":2024,"claim":"Placement of galectin-7 as a mediator of ANGPTL4-driven Hedgehog pathway modulation in gastric cancer extended its signaling repertoire to a developmental pathway in a new cancer type.","evidence":"RNA-seq, co-IP, overexpression/knockdown in gastric cancer lines, functional assays, nude mouse xenograft","pmids":["39369030"],"confidence":"Medium","gaps":["Mechanism by which galectin-7 regulates Hedgehog signaling components not defined","Single-laboratory study without independent replication","Co-IP partners within the Hedgehog pathway not specified"]},{"year":null,"claim":"The molecular mechanism by which intracellular galectin-7 activates JNK signaling — whether through a direct protein interaction or via redox intermediaries — remains unresolved, as does the structural basis for its context-dependent switch between pro-apoptotic and pro-metastatic functions.","evidence":"","pmids":[],"confidence":"High","gaps":["No direct binding partner linking galectin-7 to the JNK cascade has been identified","Structural determinants distinguishing intracellular apoptotic from extracellular lectin functions not mapped","In vivo role of HMGCS1 interaction in epidermal cholesterol homeostasis not validated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,9,12]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1,3,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,7]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,6,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,9,12]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[10]}],"complexes":[],"partners":["HMGCS1","LGALS3"],"other_free_text":[]},"mechanistic_narrative":"Galectin-7 is a homodimeric β-galactoside-binding lectin restricted to stratified squamous epithelia that functions as a p53- and UVB-inducible intracellular pro-apoptotic effector, acting upstream of JNK activation and mitochondrial cytochrome c release to sensitize cells to apoptotic stimuli [PMID:11706006, PMID:10500176, PMID:30594507]. Structurally, it adopts a conserved galectin fold with a carbohydrate-binding pocket that engages lactose, N-acetyllactosamine, and GM1 ganglioside, enabling extracellular lectin-mediated growth suppression on neuroblastoma cells [PMID:9760227, PMID:13679866]. Beyond apoptosis, galectin-7 physically interacts with HMGCS1 via phenylalanine 26, forming a positive feedback loop that drives cholesterol accumulation in keratinocytes [PMID:34454908]. In cancer contexts, galectin-7 overexpression promotes breast cancer metastasis to lungs and bones in vivo, and it mediates Hedgehog pathway regulation downstream of ANGPTL4 in gastric cancer cells [PMID:20382700, PMID:39369030]."},"prefetch_data":{"uniprot":{"accession":"P47929","full_name":"Galectin-7","aliases":["HKL-14","PI7","p53-induced gene 1 protein"],"length_aa":136,"mass_kda":15.1,"function":"Could be involved in cell-cell and/or cell-matrix interactions necessary for normal growth control. Pro-apoptotic protein that functions intracellularly upstream of JNK activation and cytochrome c release","subcellular_location":"Cytoplasm; Nucleus; Secreted","url":"https://www.uniprot.org/uniprotkb/P47929/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LGALS7","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1046,"dependency_fraction":0.0028680688336520078},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LGALS7","total_profiled":1310},"omim":[{"mim_id":"617139","title":"LECTIN, GALACTOSIDE-BINDING, SOLUBLE, 7B; LGALS7B","url":"https://www.omim.org/entry/617139"},{"mim_id":"600615","title":"LECTIN, GALACTOSIDE-BINDING, SOLUBLE, 7; LGALS7","url":"https://www.omim.org/entry/600615"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"cervix","ntpm":331.6},{"tissue":"esophagus","ntpm":613.2},{"tissue":"skin 1","ntpm":1404.3}],"url":"https://www.proteinatlas.org/search/LGALS7"},"hgnc":{"alias_symbol":["GAL7","PIG1","TP53I1","LGALS7A"],"prev_symbol":[]},"alphafold":{"accession":"P47929","domains":[{"cath_id":"2.60.120.200","chopping":"5-134","consensus_level":"high","plddt":97.3655,"start":5,"end":134}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P47929","model_url":"https://alphafold.ebi.ac.uk/files/AF-P47929-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P47929-F1-predicted_aligned_error_v6.png","plddt_mean":96.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LGALS7","jax_strain_url":"https://www.jax.org/strain/search?query=LGALS7"},"sequence":{"accession":"P47929","fasta_url":"https://rest.uniprot.org/uniprotkb/P47929.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P47929/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P47929"}},"corpus_meta":[{"pmid":"11706006","id":"PMC_11706006","title":"Galectin-7 (PIG1) exhibits pro-apoptotic function through JNK activation and mitochondrial cytochrome c release.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11706006","citation_count":173,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1429664","id":"PMC_1429664","title":"Strand-selective repair of DNA damage in the yeast GAL7 gene requires RNA polymerase II.","date":"1992","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1429664","citation_count":115,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2851900","id":"PMC_2851900","title":"Primary structure of the Saccharomyces cerevisiae GAL7 gene.","date":"1985","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/2851900","citation_count":102,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9707436","id":"PMC_9707436","title":"Poly(A) signals control both transcriptional termination and initiation between the tandem GAL10 and GAL7 genes of Saccharomyces cerevisiae.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9707436","citation_count":93,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3062381","id":"PMC_3062381","title":"Yeast regulatory gene GAL3: carbon regulation; 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\"Tier 2 — multiple orthogonal methods (apoptosis assays, cytochrome c release, JNK activity, caspase inhibitor rescue, localization) in a single rigorous study\",\n      \"pmids\": [\"11706006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Galectin-7 (Gal-7) mediates TGF-β1-induced apoptosis in bronchial epithelial cells through the JNK signaling pathway; siRNA-mediated knockdown of Gal-7 abrogated TGF-β1-evoked apoptosis and JNK phosphorylation, and this effect was reversed by the JNK activator anisomycin.\",\n      \"method\": \"siRNA knockdown, flow cytometry apoptosis assay, Western blot (Bcl-2, Bax, PARP, caspase-3, p-JNK), pharmacological rescue with anisomycin\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype and pathway placement, but single lab study\",\n      \"pmids\": [\"30594507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Gal-7 (LGALS7) physically interacts with HMGCS1 (3-hydroxy-3-methylglutaryl coenzyme A synthase 1) in keratinocytes; this interaction, mapped to phenylalanine 26 of HMGCS1, promotes HMGCS1 upregulation and downstream cholesterol accumulation in a positive feedback loop.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro β-galactosidase assay, Biacore binding assay, co-immunoprecipitation, LGALS7 siRNA knockdown, HMGCS1 peptide competition with F26 mutant, cholesterol quantification\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (Y2H, Biacore, Co-IP, mutagenesis) in single lab study\",\n      \"pmids\": [\"34454908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANGPTL4 overexpression in AGS gastric cancer cells upregulates LGALS7, which in turn regulates the Hedgehog signaling pathway to influence cancer cell proliferation, migration, apoptosis evasion, angiogenesis, and lymphangiogenesis.\",\n      \"method\": \"RNA-seq, PCR, Western blot, co-immunoprecipitation, immunofluorescence, functional cell assays (EdU, MTT, flow cytometry, wound healing, transwell, tube formation)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — co-IP and expression data link LGALS7 to Hedgehog pathway but mechanistic details of LGALS7's direct role are not fully resolved in a single study\",\n      \"pmids\": [\"39369030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LGALS7 expression is transcriptionally repressed by a nuclear complex comprising the lncRNA PANC754, RNA-binding protein PSPC1, and histone mark H3K4me1, in a manner dependent on m6A modification by METTL3; this repression reduces immune evasion in colorectal cancer.\",\n      \"method\": \"Loss/gain of function experiments, molecular docking, bioinformatic analysis, co-culture immune assays, chromatin accessibility assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic complex described but direct biochemical validation of LGALS7 regulation within this complex is limited\",\n      \"pmids\": [\"40634299\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGALS7 (galectin-7) is an intracellularly localized (nuclear and cytoplasmic) pro-apoptotic protein that promotes apoptosis by acting upstream of JNK activation and mitochondrial cytochrome c release with subsequent caspase-3 activation; it also physically interacts with HMGCS1 to promote cholesterol biosynthesis in keratinocytes, and its expression is subject to transcriptional repression by an m6A-dependent lncRNA/RBP/histone complex.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nKEEP (LGALS7 canonical protein):\n- PMID:11706006 - Galectin-7 pro-apoptotic function via JNK/cytochrome c ✓\n- PMID:10500176 - Galectin-7 overexpression in UVB-induced apoptosis ✓\n- PMID:9760227 - Crystal structure of human galectin-7 ✓\n- PMID:7534301 - Cloning/expression of human galectin-7 ✓\n- PMID:9697310 - Galectin-7 marker of stratified epithelia ✓\n- PMID:13679866 - Homodimeric galectin-7 growth regulator ✓\n- PMID:7729568 - Galectin-7 14-kDa S-lectin in keratinocytes ✓\n- PMID:20382700 - Galectin-7 in breast cancer metastasis ✓\n- PMID:30594507 - Gal-7/JNK in airway epithelial apoptosis ✓\n- PMID:34454908 - Gal-7/HMGCS1 interaction ✓\n- PMID:39369030 - ANGPTL4/LGALS7/Hedgehog pathway ✓\n- PMID:32915505 - Galectin-7 interaction with SARS-CoV-2 glycans ✓\n\nEXCLUDE (yeast GAL7 gene - galactose-1-phosphate uridyltransferase or regulatory locus):\n- PMIDs: 1429664, 2851900, 9707436, 3062381, 15531585, 6774992, 10890898, 8577246, 3023825, 2209557, 9418396 (pIG1 Streptomyces), 6324089, 11919723, 28213885, 3912516, 3302604, 9046081, 8417325, 9032299, 1677180, 1406619, 22144353, 7762304, 9226959, 21822965, 9305847 (PIG1=CDKN1A context), 12477932, 20562859, 19615732, 28514442, 32296183, 33961781, 15489334, 8889548, 21145461, 27705803, 26673895, 32203420, 33658012, 30690837, 29467282, 28977666, 24457600, 21319273, 25324306, 24981860, 78953 (various non-LGALS7 papers)\n\nC. elegans PIG-1/MELK papers: EXCLUDE (alias collision - PIG-1 is MELK ortholog, not LGALS7)\n- PMIDs: 16774992, 32946434, 28652378, 30213539, 38787850\n\nPIG1 melanocyte cell line papers (PIG1 is a melanocyte cell line name, not LGALS7 gene): EXCLUDE for non-LGALS7 mechanism\n- PMID:36924030, 38933605, 39912936, bio_10.1101_2024.05.22.595382 - these use PIG1 as melanocyte cell line\n\nScedosporium PIG1: EXCLUDE - fungal transcription factor\n- PMID:36836250\n\nPMID:9305847 - describes PIG1 as p53-induced gene including galectin-7, KEEP for context but mainly identifies LGALS7 as p53 target\n\nPMID:40634299 - PANC754/LGALS7 - this is about a ncRNA regulating LGALS7 expression, not LGALS7 mechanism directly - EXCLUDE (alt-locus product regulating LGALS7)\n\nPMID:35401111 - LGALS7 promoter SNPs - expression/association study - EXCLUDE\n\nPMID:27646625 - IHC expression study - EXCLUDE\n\nPMID:40082314 - imaging probe/expression - EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Human galectin-7 (LGALS7) was cloned from a keratinocyte cDNA library and shown to encode a 14-kDa beta-galactoside-binding protein (IEF 17) specifically expressed in stratified squamous epithelium. The protein was partially secreted to the medium despite lacking a classical signal peptide, localized to basal keratinocytes and areas of cell-to-cell contact, and the gene was mapped to chromosome 19.\",\n      \"method\": \"cDNA cloning, two-dimensional gel electrophoresis, immunoblotting, immunofluorescence, lactose-binding assay, chromosomal mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (cloning, 2D-PAGE, lectin-binding assay, immunolocalization) in a single foundational study\",\n      \"pmids\": [\"7534301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Galectin-7 is a 14-kDa S-lectin specifically expressed in keratinocytes at all stages of epidermal differentiation (basal and suprabasal layers). Its expression is moderately repressed by retinoic acid, consistent with a metaplasiogenic rather than a simple differentiation-stage effect. A GST fusion protein confirmed lactose-binding properties.\",\n      \"method\": \"cDNA cloning, differential hybridization, in situ hybridization, GST fusion protein lectin assay, retinoic acid treatment\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical lectin-binding confirmation plus multiple expression methods, replicated across species\",\n      \"pmids\": [\"7729568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Galectin-7 (designated PIG1, p53-induced gene 1) was identified as a transcriptional target of p53 in colorectal carcinoma cells, placing it downstream of p53 in a pathway involving redox-related gene induction preceding apoptosis.\",\n      \"method\": \"p53-inducible expression system, transcriptional profiling (serial analysis of gene expression/differential display), pharmacological and biochemical validation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic p53-inducible screen with functional validation, but galectin-7 is one of many identified targets\",\n      \"pmids\": [\"9305847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Crystal structure of human galectin-7 was determined in free form and bound to galactose, galactosamine, lactose, and N-acetyl-lactosamine at high resolution. The structure revealed a fold similar to prototype galectins-1 and -2 but with greater similarity to Gal-10; carbohydrate-binding residues are conserved but a shortened loop alters the binding pocket. Galectin-7 crystallizes as a dimer with a packing arrangement distinct from galectins-1 and -2, with implications for carbohydrate recognition.\",\n      \"method\": \"X-ray crystallography with multiple ligands\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure determination in free and multiple ligand-bound forms\",\n      \"pmids\": [\"9760227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Galectin-7 expression is a marker of all subtypes of stratified epithelia (interfollicular epidermis, outer root sheath, esophagus, oral epithelia, cornea, thymic Hassall's corpuscles) but is absent from simple and transitional epithelia, hair matrix, sebaceous glands, and carcinoma cell lines, establishing its specific distribution and loss in malignancy.\",\n      \"method\": \"In situ hybridization, immunolabeling of human/rat/mouse tissues, rat and mouse cDNA cloning\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic multi-tissue, multi-species characterization with consistent findings\",\n      \"pmids\": [\"9697310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Galectin-7 mRNA and protein are rapidly upregulated after UVB irradiation of epidermal keratinocytes, in parallel with p53 stabilization. In reconstructed skin and human skin ex vivo, galectin-7 overexpression is associated with sunburn/apoptotic keratinocytes. Transfection of a galectin-7 expression vector significantly increased TUNEL-positive keratinocytes, demonstrating a direct pro-apoptotic role in UV-induced apoptosis.\",\n      \"method\": \"UVB irradiation, immunofluorescence, immunoblotting, TUNEL assay, galectin-7 expression vector transfection, reconstructed skin model, human skin ex vivo\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function transfection with TUNEL readout plus ex vivo tissue model, replicated across systems\",\n      \"pmids\": [\"10500176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Galectin-7 functions as an intracellular pro-apoptotic protein, acting upstream of JNK activation and mitochondrial cytochrome c release. Ectopic expression in HeLa and DLD-1 cells enhanced susceptibility to apoptosis from mechanistically distinct stimuli. Apoptosis potentiation was associated with enhanced caspase-3 activity, PARP cleavage, accelerated cytochrome c release, and up-regulated JNK activity. The pro-apoptotic effect was blocked by pan-caspase inhibitor zVAD-fmk and was not attributable to extracellular lectin activity, as galectin-7 localizes to nuclei and cytoplasm. DNA microarray analysis revealed up-regulation of redox-related genes (monoamine oxidase B, ryanodine receptor 2, glutathione S-transferase Mu 3) in galectin-7-expressing cells.\",\n      \"method\": \"Stable transfection (HeLa, DLD-1), apoptosis assays with multiple stimuli, caspase-3 activity assay, PARP cleavage, cytochrome c release, JNK activity assay, caspase inhibitor rescue, immunofluorescence localization, DNA microarray\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods across two cell lines, pathway placement upstream of JNK and cytochrome c, pharmacological rescue\",\n      \"pmids\": [\"11706006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Extracellular galectin-7 binds the GM1 ganglioside sugar chain on the surface of neuroblastoma cells (SK-N-MC), acting as a lectin to reduce cell growth without classical apoptosis features. This effect was blocked by galectin-3, mechanistically resembling galectin-1's growth-suppressive activity despite structural differences. The protein exists as a homodimer capable of crosslinking cell-surface glycoconjugates.\",\n      \"method\": \"Solid-phase binding assay, cell proliferation assay, competition assay with galectin-3, serum-supplemented culture, neuroblastoma cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — solid-phase binding plus cell assay with competition, single lab\",\n      \"pmids\": [\"13679866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Overexpression of galectin-7 in breast cancer cells drastically increased their metastatic capacity to lungs and bones in two preclinical mouse models. This established a functional role for galectin-7 in promoting cancer metastasis in vivo, in contrast to its tumor-suppressive role in epithelial homeostasis.\",\n      \"method\": \"Stable overexpression in breast cancer cell lines, orthotopic and systemic mouse models, quantification of pulmonary metastases and osteolytic lesions, immunohistochemistry of human breast tissue\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain-of-function with two mouse models and quantitative metastasis readout\",\n      \"pmids\": [\"20382700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"siRNA-mediated knockdown of galectin-7 in bronchial epithelial cells (BEAS-2B) abrogated TGF-β1-induced apoptosis, decreased Bax expression, increased Bcl-2, and reduced caspase-3 cleavage and PARP cleavage. Gal-7 knockdown also inhibited TGF-β1-induced JNK phosphorylation. Rescue with the JNK activator anisomycin reversed the anti-apoptotic effect of Gal-7 silencing, placing galectin-7 upstream of JNK in TGF-β1-induced apoptosis in airway epithelial cells.\",\n      \"method\": \"siRNA knockdown, flow cytometry (apoptosis), western blotting (Bcl-2, Bax, caspase-3, PARP, p-JNK), anisomycin rescue experiment\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined pathway placement and pharmacological rescue, single lab\",\n      \"pmids\": [\"30594507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Galectin-7 (Gal-7) physically interacts with 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) as identified by yeast two-hybrid screening and confirmed by in vitro beta-galactosidase assay, Biacore surface plasmon resonance, and co-immunoprecipitation. The interaction site on HMGCS1 was mapped to phenylalanine 26. Exogenous Gal-7 upregulates HMGCS1 expression in keratinocytes, and LGALS7 siRNA knockdown reduces HMGCS1 and cholesterol levels. HMGCS1-overexpressing cells induce Gal-7 expression in a positive feedback loop. Gal-7-mediated cholesterol elevation was blocked by wild-type but not F26-mutated HMGCS1 peptide, linking the Gal-7/HMGCS1 interaction to cellular cholesterol accumulation.\",\n      \"method\": \"Yeast two-hybrid, in vitro beta-galactosidase assay, Biacore SPR, co-immunoprecipitation, LGALS7 siRNA knockdown, HMGCS1 overexpression, cholesterol measurement, site-directed mutagenesis (F26 mutation)\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — interaction confirmed by multiple orthogonal methods including SPR and mutagenesis mapping of interaction site\",\n      \"pmids\": [\"34454908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NMR spectroscopy demonstrated that galectin-7 interacts with glycans on the receptor-binding domain of the SARS-CoV-2 spike protein. Complementary experiments from both the glycoprotein and lectin perspectives identified specific interacting epitopes, and 3D models of the interacting complexes were proposed.\",\n      \"method\": \"NMR spectroscopy with 15N-labeled galectin-7 and 13C-labeled RBD glycans, binding epitope mapping\",\n      \"journal\": \"Angewandte Chemie (International ed. in English)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural interaction data, but functional consequences not established for galectin-7 specifically\",\n      \"pmids\": [\"32915505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In gastric cancer AGS cells, ANGPTL4 overexpression upregulates LGALS7 expression, and LGALS7 acts as a downstream mediator of ANGPTL4's anticancer phenotype. LGALS7 regulates the Hedgehog signaling pathway, and co-immunoprecipitation confirmed protein-level interactions in this context. LGALS7 was shown to influence proliferation, migration, apoptosis evasion, angiogenesis, and lymphangiogenesis downstream of ANGPTL4.\",\n      \"method\": \"RNA-seq, PCR, western blotting, co-immunoprecipitation, cell line overexpression/knockdown (SNU5, MKN7, AGS), functional assays (EdU, MTT, flow cytometry, wound healing, transwell, tube formation), nude mouse xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway placement via RNA-seq and co-IP with functional in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"39369030\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGALS7 encodes galectin-7, a 14-kDa homodimeric beta-galactoside-binding lectin specifically expressed in stratified epithelia, which functions intracellularly as a pro-apoptotic protein acting upstream of JNK activation and mitochondrial cytochrome c release (established by gain- and loss-of-function experiments), interacts with HMGCS1 at phenylalanine 26 to promote cholesterol accumulation in keratinocytes, binds GM1 ganglioside on neuroblastoma cell surfaces to suppress proliferation, and structurally engages carbohydrates through a conserved binding pocket defined by X-ray crystallography; it is transcriptionally induced by p53 and UVB, and its overexpression promotes breast cancer metastasis in vivo while its downstream signaling involves the Hedgehog pathway in gastric cancer contexts.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LGALS7 (galectin-7) is a pro-apoptotic lectin that functions intracellularly in the nucleus and cytoplasm, promoting apoptosis by acting upstream of JNK activation and mitochondrial cytochrome c release, leading to caspase-3 activation and PARP cleavage [PMID:11706006, PMID:30594507]. Beyond apoptosis, LGALS7 physically interacts with HMGCS1 in keratinocytes via phenylalanine 26 of HMGCS1, promoting HMGCS1 upregulation and downstream cholesterol accumulation in a positive feedback loop [PMID:34454908].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that galectin-7 is an intracellular pro-apoptotic effector resolved its cell-biological role: it localizes to nuclei and cytoplasm and promotes apoptosis upstream of JNK activation and mitochondrial cytochrome c release, activating caspase-3 and PARP cleavage.\",\n      \"evidence\": \"Ectopic expression in HeLa and DLD-1 cells with caspase activity assays, cytochrome c release, JNK assays, caspase inhibitor rescue, and subcellular fractionation\",\n      \"pmids\": [\"11706006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct molecular target or binding partner mediating JNK activation is unknown\",\n        \"Whether galectin-7's carbohydrate-binding activity is required for its pro-apoptotic function was not tested\",\n        \"Physiological relevance in native tissue contexts not addressed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Independent confirmation that galectin-7 mediates apoptosis through JNK signaling — here downstream of TGF-β1 in bronchial epithelial cells — solidified the JNK-dependent apoptotic mechanism and placed LGALS7 as a required mediator in a receptor-initiated apoptotic cascade.\",\n      \"evidence\": \"siRNA knockdown abrogated TGF-β1-induced apoptosis and JNK phosphorylation; rescued by the JNK activator anisomycin\",\n      \"pmids\": [\"30594507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which galectin-7 activates JNK remains unresolved\",\n        \"Single lab study; independent replication in primary bronchial cells lacking\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery of a direct physical interaction between galectin-7 and HMGCS1 in keratinocytes revealed a non-apoptotic function: galectin-7 promotes cholesterol biosynthesis via HMGCS1 upregulation in a positive feedback loop, expanding its role beyond cell death.\",\n      \"evidence\": \"Yeast two-hybrid, Biacore binding, co-immunoprecipitation, F26 mutant competition, LGALS7 siRNA knockdown with cholesterol quantification\",\n      \"pmids\": [\"34454908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether HMGCS1 interaction depends on galectin-7 lectin activity is untested\",\n        \"In vivo relevance of LGALS7-driven cholesterol accumulation in skin homeostasis not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular target through which galectin-7 activates JNK, the structural basis of its protein–protein interactions, and whether its lectin domain is dispensable for intracellular functions remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of galectin-7 in complex with JNK pathway components or HMGCS1\",\n        \"Carbohydrate-binding-independent versus lectin-dependent activities have not been dissected\",\n        \"In vivo knockout phenotypes relevant to apoptosis or cholesterol metabolism are not characterized in the primary mechanism literature\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HMGCS1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Galectin-7 is a homodimeric β-galactoside-binding lectin restricted to stratified squamous epithelia that functions as a p53- and UVB-inducible intracellular pro-apoptotic effector, acting upstream of JNK activation and mitochondrial cytochrome c release to sensitize cells to apoptotic stimuli [PMID:11706006, PMID:10500176, PMID:30594507]. Structurally, it adopts a conserved galectin fold with a carbohydrate-binding pocket that engages lactose, N-acetyllactosamine, and GM1 ganglioside, enabling extracellular lectin-mediated growth suppression on neuroblastoma cells [PMID:9760227, PMID:13679866]. Beyond apoptosis, galectin-7 physically interacts with HMGCS1 via phenylalanine 26, forming a positive feedback loop that drives cholesterol accumulation in keratinocytes [PMID:34454908]. In cancer contexts, galectin-7 overexpression promotes breast cancer metastasis to lungs and bones in vivo, and it mediates Hedgehog pathway regulation downstream of ANGPTL4 in gastric cancer cells [PMID:20382700, PMID:39369030].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of galectin-7 as a keratinocyte-specific β-galactoside-binding lectin established its tissue restriction and non-classical secretion, defining the gene's identity and expression domain.\",\n      \"evidence\": \"cDNA cloning from keratinocyte library, 2D-PAGE, lactose-binding assay, immunolocalization, and chromosomal mapping across two independent studies\",\n      \"pmids\": [\"7534301\", \"7729568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No functional role established beyond lectin activity\",\n        \"Mechanism of non-classical secretion not defined\",\n        \"Epithelial-specific transcriptional regulation not characterized\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of galectin-7 (PIG1) as a p53 transcriptional target linked it to the tumor suppressor network and suggested a role in apoptosis-related gene programs.\",\n      \"evidence\": \"p53-inducible expression system in colorectal carcinoma cells with serial analysis of gene expression\",\n      \"pmids\": [\"9305847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Galectin-7 was one of many p53-induced genes; its specific contribution to p53-mediated apoptosis was not isolated\",\n        \"Direct p53 binding to the LGALS7 promoter was not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Crystal structure determination of galectin-7 in free and ligand-bound forms defined the carbohydrate-binding pocket and revealed a distinctive dimer interface, providing the structural basis for its lectin activity.\",\n      \"evidence\": \"X-ray crystallography with galactose, galactosamine, lactose, and N-acetyllactosamine co-crystals\",\n      \"pmids\": [\"9760227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure-function relationship for intracellular (non-lectin) roles not addressed\",\n        \"Dimer interface contribution to biological activity not tested by mutagenesis\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstration that UVB-induced galectin-7 upregulation directly promotes keratinocyte apoptosis established its pro-apoptotic function in an epithelial damage context, converging with its p53 regulation.\",\n      \"evidence\": \"UVB irradiation of keratinocytes, galectin-7 overexpression vector transfection with TUNEL quantification, reconstructed skin and human skin ex vivo models\",\n      \"pmids\": [\"10500176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream apoptotic pathway mediators not identified\",\n        \"Whether lectin activity is required for apoptosis induction was not tested\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mechanistic dissection placed galectin-7's pro-apoptotic activity upstream of JNK activation and mitochondrial cytochrome c release, establishing it as an intracellular apoptosis amplifier independent of its extracellular lectin function.\",\n      \"evidence\": \"Stable transfection in HeLa and DLD-1 cells, caspase-3/PARP/cytochrome c/JNK assays, zVAD-fmk rescue, nuclear/cytoplasmic immunolocalization, DNA microarray\",\n      \"pmids\": [\"11706006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct molecular target linking galectin-7 to JNK activation not identified\",\n        \"Contribution of upregulated redox genes to apoptosis not functionally validated\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of GM1 ganglioside as an extracellular binding partner revealed a second, lectin-dependent mechanism by which galectin-7 suppresses cell growth via glycoconjugate crosslinking.\",\n      \"evidence\": \"Solid-phase binding assay for GM1, cell proliferation assay in neuroblastoma cells, competition with galectin-3\",\n      \"pmids\": [\"13679866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream signaling from GM1 crosslinking not characterized\",\n        \"Relevance to epithelial biology versus neuroblastoma-specific effect not resolved\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"In vivo demonstration that galectin-7 overexpression promotes breast cancer metastasis revealed a context-dependent oncogenic function, contrasting with its tumor-suppressive apoptotic role in normal epithelia.\",\n      \"evidence\": \"Stable overexpression in breast cancer lines, orthotopic and systemic mouse models with quantified lung and bone metastases\",\n      \"pmids\": [\"20382700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism underlying metastasis promotion not defined\",\n        \"Whether lectin activity or intracellular functions drive metastasis not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Loss-of-function validation confirmed galectin-7 is required for TGF-β1-induced apoptosis in airway epithelial cells via JNK, independently replicating the JNK-cytochrome c pathway placement in a non-cancer epithelial system.\",\n      \"evidence\": \"siRNA knockdown in BEAS-2B cells, western blot for Bax/Bcl-2/caspase-3/PARP/p-JNK, anisomycin rescue of JNK activity\",\n      \"pmids\": [\"30594507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single cell line from a single laboratory\",\n        \"Direct physical interaction between galectin-7 and JNK pathway components not shown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of HMGCS1 as a direct physical interactor at phenylalanine 26 revealed a non-lectin intracellular function of galectin-7 in cholesterol metabolism, expanding its roles beyond apoptosis.\",\n      \"evidence\": \"Yeast two-hybrid, SPR, co-IP, F26 mutagenesis, siRNA knockdown and overexpression with cholesterol quantification in keratinocytes\",\n      \"pmids\": [\"34454908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the HMGCS1 interaction operates through galectin-7's carbohydrate-binding site or an independent surface not resolved\",\n        \"Physiological consequence of altered cholesterol in keratinocytes not defined in vivo\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placement of galectin-7 as a mediator of ANGPTL4-driven Hedgehog pathway modulation in gastric cancer extended its signaling repertoire to a developmental pathway in a new cancer type.\",\n      \"evidence\": \"RNA-seq, co-IP, overexpression/knockdown in gastric cancer lines, functional assays, nude mouse xenograft\",\n      \"pmids\": [\"39369030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which galectin-7 regulates Hedgehog signaling components not defined\",\n        \"Single-laboratory study without independent replication\",\n        \"Co-IP partners within the Hedgehog pathway not specified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which intracellular galectin-7 activates JNK signaling — whether through a direct protein interaction or via redox intermediaries — remains unresolved, as does the structural basis for its context-dependent switch between pro-apoptotic and pro-metastatic functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct binding partner linking galectin-7 to the JNK cascade has been identified\",\n        \"Structural determinants distinguishing intracellular apoptotic from extracellular lectin functions not mapped\",\n        \"In vivo role of HMGCS1 interaction in epidermal cholesterol homeostasis not validated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 9, 12]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1, 3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 6, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 9, 12]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HMGCS1\",\n      \"LGALS3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}