{"gene":"SLC2A6","run_date":"2026-06-10T07:46:33","timeline":{"discoveries":[{"year":2022,"finding":"Slc2a6 knockdown (RNAi) in C2C12 myoblasts impaired differentiation and myotube formation; combined transcriptomics and metabolomics showed that Slc2a6 regulates myogenic differentiation partly through the glycolysis pathway by targeting LDHB, affecting lactic acid accumulation.","method":"RNAi knockdown combined with RNA-seq transcriptomics and metabolomics in C2C12 myoblasts; phenotypic readouts of differentiation and myotube formation","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with defined cellular phenotype, supported by two orthogonal omics methods (transcriptomics + metabolomics) in a single lab","pmids":["35850889"],"is_preprint":false},{"year":2020,"finding":"RELA (NF-κB subunit) directly regulates GLUT6 (SLC2A6) gene expression in endometrial cells: overexpression of constitutively active RELA increased SLC2A6 expression, while dominant-negative RELA decreased it; TNFα treatment activated NF-κB signaling and specifically increased GLUT6 expression but not that of other glucose transporters.","method":"Overexpression of constitutively active and dominant-negative RELA constructs in endometrial cells; Western blotting and RT-qPCR; TNFα stimulation; transcriptome PCR array","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function of transcriptional regulator with specific phenotypic readout, single lab, two orthogonal methods (Western blot + RT-qPCR)","pmids":["32512041"],"is_preprint":false},{"year":2018,"finding":"GLUT6 (Slc2a6) knockout mice generated by CRISPR-Cas9 showed no alteration in mouse development, growth, or whole-body glucose metabolism under chow or Western diet, establishing that GLUT6 is not a major regulator of whole-body metabolic physiology; minor effects were observed in female mice (reduced fat accumulation on Western diet, lower respiratory exchange ratio on chow diet).","method":"CRISPR-Cas9 Slc2a6 knockout mice; glucose tolerance tests, blood glucose and insulin measurements, body composition analysis","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — clean CRISPR knockout with comprehensive metabolic phenotyping across multiple conditions and sexes, single lab but rigorous experimental design","pmids":["29664675"],"is_preprint":false},{"year":2022,"finding":"In GLUT6 knockout ob/ob mice, pancreatic islets secreted more insulin in response to high-dose glucose compared to ob/ob wild-type mice, demonstrating that GLUT6 plays a role in restraining pancreatic islet insulin secretion in the context of obesity.","method":"GLUT6 knockout mice crossed with ob/ob mice; ex vivo pancreatic islet glucose-stimulated insulin secretion assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic knockout with defined functional phenotype (insulin secretion assay), single lab, single method","pmids":["36077188"],"is_preprint":false},{"year":2016,"finding":"SLC2A6 (GLUT6) siRNA knockdown in HUVEC did not reduce 14C-deoxy-glucose uptake, in contrast to GLUT1 and GLUT3 knockdowns which each reduced transport by ~60%; establishing that GLUT6 does not contribute substantially to basal glucose uptake in endothelial cells.","method":"siRNA knockdown of SLC2A6 in human umbilical vein endothelial cells (HUVEC); 14C-deoxy-glucose uptake assay","journal":"Vascular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional knockdown with transport assay readout; negative result for SLC2A6 but mechanistically informative; single lab, single method","pmids":["27825869"],"is_preprint":false},{"year":2024,"finding":"Overexpression of SLC2A6 in breast cancer cells inhibited proliferation, promoted mitochondrial damage, and induced apoptosis; the HSP70 family member HSPA6 was identified as a binding partner of SLC2A6 by protein profiling, with HSPA6 levels increasing with SLC2A6 overexpression.","method":"SLC2A6 overexpression in vitro and in vivo; RNA-sequencing and protein profiling; co-expression/binding analysis identifying HSPA6 as a binding partner; proliferation and apoptosis assays","journal":"Apoptosis : an international journal on programmed cell death","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression with phenotypic readout and protein profiling suggesting HSPA6 interaction, but binding was not confirmed by reciprocal Co-IP or pulldown; single lab","pmids":["38622369"],"is_preprint":false},{"year":2025,"finding":"SLC2A6 knockout in hepatocellular carcinoma (LIHC) cells suppressed proliferation, migration, and invasion, with this inhibition closely tied to the ferroptosis pathway, as assessed by GO/KEGG enrichment and in vitro/in vivo functional experiments.","method":"SLC2A6 knockdown/knockout in HCC cell lines; in vitro proliferation, migration and invasion assays; in vivo xenograft experiments; GO/KEGG pathway enrichment analysis","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — loss-of-function with phenotypic readout and pathway association, but ferroptosis pathway placement relies on enrichment analysis rather than direct mechanistic reconstitution; single lab","pmids":["39833197"],"is_preprint":false},{"year":2026,"finding":"Slc2a6 in Kupffer cells compromises host defense against Streptococcus pneumoniae by downregulating anti-phosphorylcholine natural antibodies in serum, thereby inhibiting complement activation via the natural-antibody-mediated classical pathway and reducing bacterial opsonization and capture by Kupffer cells.","method":"Slc2a6 genetic loss-of-function in Kupffer cells; in vivo bacteremia model; serum natural antibody quantification; complement activation assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic loss-of-function with defined immunological mechanism (natural antibody levels, complement activation), multiple functional readouts, single lab","pmids":["41904952"],"is_preprint":false},{"year":2023,"finding":"In Japanese flounder (Paralichthys olivaceus), slc2a6 expression was upregulated after lymphocystis disease virus (LCDV) stimulation in vitro and in vivo (spleen and muscle); overexpression and silencing experiments showed that slc2a6 modulates NF-κB signaling pathway genes (il-1β, il-6, nf-κb, tnf-α), indicating involvement in innate immune regulation. Subcellular localization showed Slc2a6 in both nucleus and cytoplasm.","method":"pcDNA3.1-slc2a6 overexpression plasmid transfection; siRNA silencing; LCDV viral stimulation in vitro and in vivo; RT-qPCR for NF-κB pathway genes; subcellular localization assay","journal":"Fish & shellfish immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — fish ortholog, single lab; overexpression and silencing show pathway modulation but mechanism of how SLC2A6 regulates NF-κB genes is not directly established","pmids":["37838208"],"is_preprint":false}],"current_model":"SLC2A6 (GLUT6) is a facilitative glucose transporter family member whose expression is regulated by NF-κB/RELA signaling; it plays roles in myoblast differentiation via the LDHB-glycolysis axis, in restraining pancreatic islet insulin secretion under obese conditions, in Kupffer cell-mediated innate immunity by modulating natural antibody levels and complement activation, and in cancer cell proliferation and ferroptosis, though it is dispensable for whole-body glucose homeostasis."},"narrative":{"mechanistic_narrative":"SLC2A6 (GLUT6) is a facilitative glucose transporter family member that functions less as a bulk glucose importer than as a context-dependent regulator of glycolytic and immune programs across multiple tissues [PMID:29664675, PMID:27825869]. Genetic ablation in mice produces no defect in development, growth, or whole-body glucose metabolism, and siRNA knockdown in endothelial cells fails to reduce deoxy-glucose uptake, establishing that GLUT6 is dispensable for basal glucose transport and systemic glucose homeostasis [PMID:29664675, PMID:27825869]. Its expression is induced by NF-κB signaling: constitutively active RELA and TNFα stimulation specifically upregulate SLC2A6 among glucose transporters, while dominant-negative RELA suppresses it [PMID:32512041]. Functionally, SLC2A6 supports myoblast differentiation through a glycolytic LDHB-dependent axis controlling lactate accumulation [PMID:35850889], and restrains glucose-stimulated insulin secretion from pancreatic islets in the obese (ob/ob) state [PMID:36077188]. In innate immunity, Kupffer-cell SLC2A6 compromises host defense against Streptococcus pneumoniae by downregulating anti-phosphorylcholine natural antibodies, thereby limiting classical-pathway complement activation and bacterial opsonization [PMID:41904952]. Beyond these roles, the molecular mechanism by which SLC2A6 couples to these downstream pathways—and whether it acts as a transporter in each context—has not been resolved in the available corpus.","teleology":[{"year":2016,"claim":"Testing whether GLUT6 contributes to cellular glucose uptake addressed the basic assumption that this transporter family member moves glucose; the result reframed SLC2A6 as functionally distinct from canonical glucose transporters.","evidence":"siRNA knockdown of SLC2A6 versus GLUT1/GLUT3 with 14C-deoxy-glucose uptake assay in HUVEC","pmids":["27825869"],"confidence":"Medium","gaps":["A negative uptake result does not establish what SLC2A6 does transport, if anything","Limited to endothelial cells under basal conditions"]},{"year":2018,"claim":"A clean knockout tested whether GLUT6 is required for organismal glucose physiology; its dispensability established that GLUT6 is not a major systemic metabolic regulator and redirected attention to tissue-specific roles.","evidence":"CRISPR-Cas9 Slc2a6 knockout mice with glucose tolerance, insulin, and body composition phenotyping under chow and Western diet","pmids":["29664675"],"confidence":"High","gaps":["Does not exclude tissue-restricted or condition-specific functions","Sex-specific minor effects (female fat accumulation, RER) left unexplained mechanistically"]},{"year":2020,"claim":"Identifying RELA as a direct upstream activator answered how SLC2A6 expression is controlled, linking it specifically to NF-κB/inflammatory signaling rather than general metabolic regulation.","evidence":"Constitutively active and dominant-negative RELA overexpression plus TNFα stimulation with Western blot and RT-qPCR in endometrial cells","pmids":["32512041"],"confidence":"Medium","gaps":["Direct promoter binding/occupancy not demonstrated","Functional consequence of NF-κB-driven SLC2A6 induction not tested in this system"]},{"year":2022,"claim":"Knockdown in myoblasts connected SLC2A6 to a differentiation program, showing it acts through glycolysis via LDHB rather than as a passive transporter.","evidence":"RNAi knockdown with paired transcriptomics and metabolomics and differentiation/myotube readouts in C2C12 cells","pmids":["35850889"],"confidence":"Medium","gaps":["Mechanistic link between SLC2A6 and LDHB regulation not defined","Whether transport activity is required for the differentiation phenotype unknown"]},{"year":2022,"claim":"Crossing the knockout onto an obese background revealed a conditional role: GLUT6 restrains islet insulin secretion specifically under obesity, exposing a function invisible in lean animals.","evidence":"Slc2a6 knockout x ob/ob mice with ex vivo glucose-stimulated insulin secretion assay","pmids":["36077188"],"confidence":"Medium","gaps":["Cell-autonomous beta-cell mechanism not established","Single functional readout in one genetic background"]},{"year":2024,"claim":"Overexpression in breast cancer cells tied SLC2A6 to proliferation control and a candidate protein partner, suggesting a non-transport, interaction-based mode of action.","evidence":"SLC2A6 overexpression with RNA-seq, protein profiling identifying HSPA6, and proliferation/apoptosis assays","pmids":["38622369"],"confidence":"Low","gaps":["HSPA6 interaction not confirmed by reciprocal Co-IP or pulldown","Overexpression phenotype may not reflect endogenous function","Direction of effect (tumor-suppressive) conflicts with HCC findings"]},{"year":2025,"claim":"Loss-of-function in hepatocellular carcinoma cells linked SLC2A6 to tumor aggressiveness through ferroptosis, indicating a pro-proliferative role in this cancer context.","evidence":"SLC2A6 knockdown/knockout with proliferation/migration/invasion assays, xenografts, and GO/KEGG enrichment","pmids":["39833197"],"confidence":"Low","gaps":["Ferroptosis link rests on enrichment analysis, not direct mechanistic reconstitution","No molecular pathway connecting SLC2A6 to ferroptosis effectors"]},{"year":2026,"claim":"Kupffer-cell loss-of-function defined a concrete innate-immune mechanism, showing SLC2A6 suppresses natural antibodies and complement-mediated bacterial clearance.","evidence":"Slc2a6 genetic loss-of-function in Kupffer cells with in vivo bacteremia, serum natural antibody quantification, and complement activation assays","pmids":["41904952"],"confidence":"Medium","gaps":["Molecular link between SLC2A6 activity and natural-antibody levels unresolved","Whether transport function underlies the immune phenotype unknown"]},{"year":null,"claim":"The core biochemical activity of SLC2A6—its physiological substrate and how transport (or a non-transport function) couples to NF-κB induction, glycolytic LDHB control, insulin secretion, and immune regulation—remains unresolved.","evidence":"No discovery in the corpus reconstitutes SLC2A6 transport activity or directly links it mechanistically to its downstream phenotypes","pmids":[],"confidence":"Low","gaps":["No defined transported substrate","No structural model","Mechanistic unification across metabolic, cancer, and immune roles absent"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7]}],"complexes":[],"partners":["HSPA6","RELA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UGQ3","full_name":"Solute carrier family 2, facilitated glucose transporter member 6","aliases":["Glucose transporter type 6","GLUT-6"],"length_aa":507,"mass_kda":54.5,"function":"Probable sugar transporter that acts as a regulator of glycolysis in macrophages (Probable). Does not transport glucose (PubMed:30431159)","subcellular_location":"Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9UGQ3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC2A6","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC2A6","total_profiled":1310},"omim":[{"mim_id":"606813","title":"SOLUTE CARRIER FAMILY 2i (FACILITATED GLUCOSE TRANSPORTER), MEMBER 6; SLC2A6","url":"https://www.omim.org/entry/606813"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":17.6},{"tissue":"lymphoid tissue","ntpm":13.5}],"url":"https://www.proteinatlas.org/search/SLC2A6"},"hgnc":{"alias_symbol":["GLUT9","GLUT6","HSA011372"],"prev_symbol":[]},"alphafold":{"accession":"Q9UGQ3","domains":[{"cath_id":"1.20.1250.20","chopping":"33-215_261-366_393-501","consensus_level":"medium","plddt":88.0009,"start":33,"end":501}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UGQ3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UGQ3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UGQ3-F1-predicted_aligned_error_v6.png","plddt_mean":81.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC2A6","jax_strain_url":"https://www.jax.org/strain/search?query=SLC2A6"},"sequence":{"accession":"Q9UGQ3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UGQ3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UGQ3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UGQ3"}},"corpus_meta":[{"pmid":"18174209","id":"PMC_18174209","title":"Species differences in Cl- affinity and in electrogenicity of SLC26A6-mediated oxalate/Cl- exchange correlate with the distinct human and mouse susceptibilities to nephrolithiasis.","date":"2008","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18174209","citation_count":61,"is_preprint":false},{"pmid":"33688234","id":"PMC_33688234","title":"Identification of Potential Early Diagnostic Biomarkers of Sepsis.","date":"2021","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/33688234","citation_count":37,"is_preprint":false},{"pmid":"37735250","id":"PMC_37735250","title":"GCH1 reduces LPS-induced alveolar macrophage polarization and inflammation by inhibition of ferroptosis.","date":"2023","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/37735250","citation_count":28,"is_preprint":false},{"pmid":"27825869","id":"PMC_27825869","title":"Transendothelial glucose transport is not restricted by extracellular hyperglycaemia.","date":"2016","source":"Vascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27825869","citation_count":28,"is_preprint":false},{"pmid":"33276199","id":"PMC_33276199","title":"Fibronectin-functionalization of 3D collagen networks supports immune tolerance and inflammation suppression in human monocyte-derived macrophages.","date":"2020","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/33276199","citation_count":27,"is_preprint":false},{"pmid":"29664675","id":"PMC_29664675","title":"Knockout of glucose transporter GLUT6 has minimal effects on whole body metabolic physiology in mice.","date":"2018","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/29664675","citation_count":26,"is_preprint":false},{"pmid":"31395793","id":"PMC_31395793","title":"Frailty in middle age is associated with frailty status and race-specific changes to the transcriptome.","date":"2019","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31395793","citation_count":24,"is_preprint":false},{"pmid":"38390208","id":"PMC_38390208","title":"Dysregulation of ferroptosis-related genes in granulosa cells associates with impaired oocyte quality in polycystic ovary syndrome.","date":"2024","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/38390208","citation_count":23,"is_preprint":false},{"pmid":"32512041","id":"PMC_32512041","title":"The NF-κB signalling pathway regulates GLUT6 expression in endometrial cancer.","date":"2020","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/32512041","citation_count":23,"is_preprint":false},{"pmid":"30972876","id":"PMC_30972876","title":"Three novel genetic variants in NRF2 signaling pathway genes are associated with pancreatic cancer risk.","date":"2019","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/30972876","citation_count":21,"is_preprint":false},{"pmid":"22530001","id":"PMC_22530001","title":"Transcriptional profiling of formalin fixed paraffin embedded tissue: pitfalls and recommendations for identifying biologically relevant changes.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22530001","citation_count":20,"is_preprint":false},{"pmid":"35205354","id":"PMC_35205354","title":"Identification of Candidate Genes for Meat Color of Chicken by Combing Selection Signature Analyses and Differentially Expressed Genes.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/35205354","citation_count":14,"is_preprint":false},{"pmid":"32013205","id":"PMC_32013205","title":"Analysis of De Novo Mutations in Sporadic Cardiomyopathies Emphasizes Their Clinical Relevance and Points to Novel Candidate Genes.","date":"2020","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32013205","citation_count":14,"is_preprint":false},{"pmid":"35850889","id":"PMC_35850889","title":"Slc2a6 regulates myoblast differentiation by targeting LDHB.","date":"2022","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/35850889","citation_count":9,"is_preprint":false},{"pmid":"38148933","id":"PMC_38148933","title":"Expressions of glucose transporter genes are diversely attenuated and significantly associated with prostate cancer progression.","date":"2023","source":"American journal of clinical and experimental 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metabolomics showed that Slc2a6 regulates myogenic differentiation partly through the glycolysis pathway by targeting LDHB, affecting lactic acid accumulation.\",\n      \"method\": \"RNAi knockdown combined with RNA-seq transcriptomics and metabolomics in C2C12 myoblasts; phenotypic readouts of differentiation and myotube formation\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with defined cellular phenotype, supported by two orthogonal omics methods (transcriptomics + metabolomics) in a single lab\",\n      \"pmids\": [\"35850889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RELA (NF-κB subunit) directly regulates GLUT6 (SLC2A6) gene expression in endometrial cells: overexpression of constitutively active RELA increased SLC2A6 expression, while dominant-negative RELA decreased it; TNFα treatment activated NF-κB signaling and specifically increased GLUT6 expression but not that of other glucose transporters.\",\n      \"method\": \"Overexpression of constitutively active and dominant-negative RELA constructs in endometrial cells; Western blotting and RT-qPCR; TNFα stimulation; transcriptome PCR array\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function of transcriptional regulator with specific phenotypic readout, single lab, two orthogonal methods (Western blot + RT-qPCR)\",\n      \"pmids\": [\"32512041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GLUT6 (Slc2a6) knockout mice generated by CRISPR-Cas9 showed no alteration in mouse development, growth, or whole-body glucose metabolism under chow or Western diet, establishing that GLUT6 is not a major regulator of whole-body metabolic physiology; minor effects were observed in female mice (reduced fat accumulation on Western diet, lower respiratory exchange ratio on chow diet).\",\n      \"method\": \"CRISPR-Cas9 Slc2a6 knockout mice; glucose tolerance tests, blood glucose and insulin measurements, body composition analysis\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — clean CRISPR knockout with comprehensive metabolic phenotyping across multiple conditions and sexes, single lab but rigorous experimental design\",\n      \"pmids\": [\"29664675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In GLUT6 knockout ob/ob mice, pancreatic islets secreted more insulin in response to high-dose glucose compared to ob/ob wild-type mice, demonstrating that GLUT6 plays a role in restraining pancreatic islet insulin secretion in the context of obesity.\",\n      \"method\": \"GLUT6 knockout mice crossed with ob/ob mice; ex vivo pancreatic islet glucose-stimulated insulin secretion assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic knockout with defined functional phenotype (insulin secretion assay), single lab, single method\",\n      \"pmids\": [\"36077188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SLC2A6 (GLUT6) siRNA knockdown in HUVEC did not reduce 14C-deoxy-glucose uptake, in contrast to GLUT1 and GLUT3 knockdowns which each reduced transport by ~60%; establishing that GLUT6 does not contribute substantially to basal glucose uptake in endothelial cells.\",\n      \"method\": \"siRNA knockdown of SLC2A6 in human umbilical vein endothelial cells (HUVEC); 14C-deoxy-glucose uptake assay\",\n      \"journal\": \"Vascular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional knockdown with transport assay readout; negative result for SLC2A6 but mechanistically informative; single lab, single method\",\n      \"pmids\": [\"27825869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Overexpression of SLC2A6 in breast cancer cells inhibited proliferation, promoted mitochondrial damage, and induced apoptosis; the HSP70 family member HSPA6 was identified as a binding partner of SLC2A6 by protein profiling, with HSPA6 levels increasing with SLC2A6 overexpression.\",\n      \"method\": \"SLC2A6 overexpression in vitro and in vivo; RNA-sequencing and protein profiling; co-expression/binding analysis identifying HSPA6 as a binding partner; proliferation and apoptosis assays\",\n      \"journal\": \"Apoptosis : an international journal on programmed cell death\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression with phenotypic readout and protein profiling suggesting HSPA6 interaction, but binding was not confirmed by reciprocal Co-IP or pulldown; single lab\",\n      \"pmids\": [\"38622369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC2A6 knockout in hepatocellular carcinoma (LIHC) cells suppressed proliferation, migration, and invasion, with this inhibition closely tied to the ferroptosis pathway, as assessed by GO/KEGG enrichment and in vitro/in vivo functional experiments.\",\n      \"method\": \"SLC2A6 knockdown/knockout in HCC cell lines; in vitro proliferation, migration and invasion assays; in vivo xenograft experiments; GO/KEGG pathway enrichment analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — loss-of-function with phenotypic readout and pathway association, but ferroptosis pathway placement relies on enrichment analysis rather than direct mechanistic reconstitution; single lab\",\n      \"pmids\": [\"39833197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Slc2a6 in Kupffer cells compromises host defense against Streptococcus pneumoniae by downregulating anti-phosphorylcholine natural antibodies in serum, thereby inhibiting complement activation via the natural-antibody-mediated classical pathway and reducing bacterial opsonization and capture by Kupffer cells.\",\n      \"method\": \"Slc2a6 genetic loss-of-function in Kupffer cells; in vivo bacteremia model; serum natural antibody quantification; complement activation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic loss-of-function with defined immunological mechanism (natural antibody levels, complement activation), multiple functional readouts, single lab\",\n      \"pmids\": [\"41904952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In Japanese flounder (Paralichthys olivaceus), slc2a6 expression was upregulated after lymphocystis disease virus (LCDV) stimulation in vitro and in vivo (spleen and muscle); overexpression and silencing experiments showed that slc2a6 modulates NF-κB signaling pathway genes (il-1β, il-6, nf-κb, tnf-α), indicating involvement in innate immune regulation. Subcellular localization showed Slc2a6 in both nucleus and cytoplasm.\",\n      \"method\": \"pcDNA3.1-slc2a6 overexpression plasmid transfection; siRNA silencing; LCDV viral stimulation in vitro and in vivo; RT-qPCR for NF-κB pathway genes; subcellular localization assay\",\n      \"journal\": \"Fish & shellfish immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — fish ortholog, single lab; overexpression and silencing show pathway modulation but mechanism of how SLC2A6 regulates NF-κB genes is not directly established\",\n      \"pmids\": [\"37838208\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC2A6 (GLUT6) is a facilitative glucose transporter family member whose expression is regulated by NF-κB/RELA signaling; it plays roles in myoblast differentiation via the LDHB-glycolysis axis, in restraining pancreatic islet insulin secretion under obese conditions, in Kupffer cell-mediated innate immunity by modulating natural antibody levels and complement activation, and in cancer cell proliferation and ferroptosis, though it is dispensable for whole-body glucose homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC2A6 (GLUT6) is a facilitative glucose transporter family member that functions less as a bulk glucose importer than as a context-dependent regulator of glycolytic and immune programs across multiple tissues [#2, #4]. Genetic ablation in mice produces no defect in development, growth, or whole-body glucose metabolism, and siRNA knockdown in endothelial cells fails to reduce deoxy-glucose uptake, establishing that GLUT6 is dispensable for basal glucose transport and systemic glucose homeostasis [#2, #4]. Its expression is induced by NF-\\u03baB signaling: constitutively active RELA and TNF\\u03b1 stimulation specifically upregulate SLC2A6 among glucose transporters, while dominant-negative RELA suppresses it [#1]. Functionally, SLC2A6 supports myoblast differentiation through a glycolytic LDHB-dependent axis controlling lactate accumulation [#0], and restrains glucose-stimulated insulin secretion from pancreatic islets in the obese (ob/ob) state [#3]. In innate immunity, Kupffer-cell SLC2A6 compromises host defense against Streptococcus pneumoniae by downregulating anti-phosphorylcholine natural antibodies, thereby limiting classical-pathway complement activation and bacterial opsonization [#7]. Beyond these roles, the molecular mechanism by which SLC2A6 couples to these downstream pathways\\u2014and whether it acts as a transporter in each context\\u2014has not been resolved in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Testing whether GLUT6 contributes to cellular glucose uptake addressed the basic assumption that this transporter family member moves glucose; the result reframed SLC2A6 as functionally distinct from canonical glucose transporters.\",\n      \"evidence\": \"siRNA knockdown of SLC2A6 versus GLUT1/GLUT3 with 14C-deoxy-glucose uptake assay in HUVEC\",\n      \"pmids\": [\"27825869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"A negative uptake result does not establish what SLC2A6 does transport, if anything\", \"Limited to endothelial cells under basal conditions\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A clean knockout tested whether GLUT6 is required for organismal glucose physiology; its dispensability established that GLUT6 is not a major systemic metabolic regulator and redirected attention to tissue-specific roles.\",\n      \"evidence\": \"CRISPR-Cas9 Slc2a6 knockout mice with glucose tolerance, insulin, and body composition phenotyping under chow and Western diet\",\n      \"pmids\": [\"29664675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not exclude tissue-restricted or condition-specific functions\", \"Sex-specific minor effects (female fat accumulation, RER) left unexplained mechanistically\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying RELA as a direct upstream activator answered how SLC2A6 expression is controlled, linking it specifically to NF-\\u03baB/inflammatory signaling rather than general metabolic regulation.\",\n      \"evidence\": \"Constitutively active and dominant-negative RELA overexpression plus TNF\\u03b1 stimulation with Western blot and RT-qPCR in endometrial cells\",\n      \"pmids\": [\"32512041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter binding/occupancy not demonstrated\", \"Functional consequence of NF-\\u03baB-driven SLC2A6 induction not tested in this system\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Knockdown in myoblasts connected SLC2A6 to a differentiation program, showing it acts through glycolysis via LDHB rather than as a passive transporter.\",\n      \"evidence\": \"RNAi knockdown with paired transcriptomics and metabolomics and differentiation/myotube readouts in C2C12 cells\",\n      \"pmids\": [\"35850889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between SLC2A6 and LDHB regulation not defined\", \"Whether transport activity is required for the differentiation phenotype unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Crossing the knockout onto an obese background revealed a conditional role: GLUT6 restrains islet insulin secretion specifically under obesity, exposing a function invisible in lean animals.\",\n      \"evidence\": \"Slc2a6 knockout x ob/ob mice with ex vivo glucose-stimulated insulin secretion assay\",\n      \"pmids\": [\"36077188\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-autonomous beta-cell mechanism not established\", \"Single functional readout in one genetic background\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Overexpression in breast cancer cells tied SLC2A6 to proliferation control and a candidate protein partner, suggesting a non-transport, interaction-based mode of action.\",\n      \"evidence\": \"SLC2A6 overexpression with RNA-seq, protein profiling identifying HSPA6, and proliferation/apoptosis assays\",\n      \"pmids\": [\"38622369\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"HSPA6 interaction not confirmed by reciprocal Co-IP or pulldown\", \"Overexpression phenotype may not reflect endogenous function\", \"Direction of effect (tumor-suppressive) conflicts with HCC findings\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Loss-of-function in hepatocellular carcinoma cells linked SLC2A6 to tumor aggressiveness through ferroptosis, indicating a pro-proliferative role in this cancer context.\",\n      \"evidence\": \"SLC2A6 knockdown/knockout with proliferation/migration/invasion assays, xenografts, and GO/KEGG enrichment\",\n      \"pmids\": [\"39833197\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Ferroptosis link rests on enrichment analysis, not direct mechanistic reconstitution\", \"No molecular pathway connecting SLC2A6 to ferroptosis effectors\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Kupffer-cell loss-of-function defined a concrete innate-immune mechanism, showing SLC2A6 suppresses natural antibodies and complement-mediated bacterial clearance.\",\n      \"evidence\": \"Slc2a6 genetic loss-of-function in Kupffer cells with in vivo bacteremia, serum natural antibody quantification, and complement activation assays\",\n      \"pmids\": [\"41904952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between SLC2A6 activity and natural-antibody levels unresolved\", \"Whether transport function underlies the immune phenotype unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The core biochemical activity of SLC2A6\\u2014its physiological substrate and how transport (or a non-transport function) couples to NF-\\u03baB induction, glycolytic LDHB control, insulin secretion, and immune regulation\\u2014remains unresolved.\",\n      \"evidence\": \"No discovery in the corpus reconstitutes SLC2A6 transport activity or directly links it mechanistically to its downstream phenotypes\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No defined transported substrate\", \"No structural model\", \"Mechanistic unification across metabolic, cancer, and immune roles absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HSPA6\", \"RELA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}