{"gene":"SLC38A6","run_date":"2026-06-10T07:46:33","timeline":{"discoveries":[{"year":2014,"finding":"SLC38A6 (SNAT6) is expressed selectively in excitatory neurons (not astrocytes) of the mouse brain and localizes to synaptic membranes, as established by immunohistochemistry and proximity ligation assay with proteins of known synaptic localization.","method":"Immunohistochemistry; proximity ligation assay (PLA) with synaptic marker proteins","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by IHC and PLA with functional context (synaptic membrane), single lab, two orthogonal methods","pmids":["24752331"],"is_preprint":false},{"year":2021,"finding":"SNAT6/SLC38A6 functions as a glutamine and glutamate transporter (demonstrated by tritium-labeled amino acid uptake assays), localizes to caveolin-rich sites at the plasma membrane, and undergoes substrate-dependent (glutamine/glutamate-triggered), sodium-dependent internalization via formation of SNAT6-caveolin complexes.","method":"Tritium-labeled amino acid transport assay; homology modeling (7 predicted TM segments); co-immunoprecipitation/proximity ligation assay for SNAT6-caveolin interaction; immunolabeling and co-localization analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transport assay with radiolabeled substrates plus PLA/co-IP for complex formation, single lab, multiple orthogonal methods","pmids":["33503881"],"is_preprint":false},{"year":2021,"finding":"SNAT6/SLC38A6 interacts with phosphate-activated glutaminase (Pag), synaptophysin, CTP synthase 2 (CTPs2), and metabotropic glutamate receptor 2 (Grm2) at the pre-synaptic terminal, suggesting it participates in the glutamate-glutamine cycle by cycling between cytoplasm and plasma membrane depending on substrate availability.","method":"Co-expression analysis; immunolabeling with co-localization analysis; proximity ligation assay (PLA)","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — PLA and co-localization are indirect interaction methods, single lab, multiple targets tested","pmids":["33503881"],"is_preprint":false},{"year":2022,"finding":"SLC38A6 expression in hepatocellular carcinoma cells is regulated epigenetically: EP300 histone acetyltransferase mediates H3K27 acetylation at the SLC38A6 promoter, and silencing EP300 reduces H3K27ac occupancy at the promoter and decreases SLC38A6 expression. SLC38A6 knockdown inhibits glutamine metabolism and mitochondrial respiration in HCC cells.","method":"Chromatin immunoprecipitation (ChIP) assay; luminescence assay for EP300-SLC38A6 interaction; siRNA knockdown; metabolic assays (glutamine metabolism, mitochondrial respiration)","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional validation by KD/OE, single lab, two orthogonal methods","pmids":["35901507"],"is_preprint":false},{"year":2023,"finding":"SLC38A6 expression in macrophages is upregulated downstream of TLR4 signaling: blocking TLR4 with TAK242 or Tlr4 knockout reduces Slc38a6 expression in macrophages. Conversely, Slc38a6 knockout (systemic or macrophage-specific via LyzCre) reduces pro-inflammatory cytokine expression (TNF-α, IL-1β) and monocyte numbers in pulmonary inflammation models, placing SLC38A6 downstream of TLR4 and upstream of IL-1β production.","method":"Conditional (LyzCRE) and systemic knockout mice; TLR4 inhibitor (TAK242); TLR4 knockout macrophages; flow cytometry; cytokine measurement (ELISA/qPCR); LPS-induced sepsis model","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via conditional KO plus pharmacological inhibition in two orthogonal models, single lab","pmids":["36707853"],"is_preprint":false},{"year":2025,"finding":"ZNF652 transcriptionally activates circRHOT1, which in turn recruits KAT5 histone acetyltransferase to the SLC38A6 promoter, increasing H3K27ac enrichment and activating SLC38A6 expression, thereby promoting HCC cell proliferation and inhibiting apoptosis.","method":"ChIP assay (H3K27ac, KAT5 occupancy at SLC38A6 promoter); siRNA knockdown; overexpression rescue experiments; luciferase/binding assays for ZNF652-circRHOT1 promoter interaction","journal":"The Kaohsiung journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for epigenetic regulation combined with rescue experiments, single lab, multiple orthogonal methods","pmids":["41311269"],"is_preprint":false},{"year":2026,"finding":"SLC38A6 deficiency in renal tubular cells alleviates cisplatin-induced acute kidney injury by decreasing tubular cell apoptosis and promoting fatty acid β-oxidation (FAO): tubular-specific Slc38a6 knockout mice show reduced lipid deposition and increased expression of key FAO enzymes, placing SLC38A6 as a suppressor of FAO and promoter of apoptosis in this context.","method":"Conditional tubular-specific knockout (Slc38a6fl/fl × KspCre); siRNA knockdown in HK-2 cells; transcriptome sequencing; Oil Red O staining (lipid deposition); Western blot and RT-qPCR for FAO enzymes; TUNEL staining; renal function assays (BUN, creatinine)","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific conditional KO with transcriptome sequencing, validated in parallel in human cell line KD, multiple orthogonal readouts","pmids":["41885504"],"is_preprint":false}],"current_model":"SLC38A6 (SNAT6) is a glutamine/glutamate transporter expressed at excitatory neuronal synapses that cycles between the plasma membrane and cytoplasm in a substrate- and sodium-dependent manner via caveolin complexes, participates in the glutamate-glutamine cycle through interactions with Pag, synaptophysin, CTPs2, and Grm2, is transcriptionally regulated by EP300-mediated H3K27ac and by the ZNF652-circRHOT1-KAT5 axis, acts downstream of TLR4 signaling in macrophages to promote pro-inflammatory cytokine production, and in renal tubular cells promotes apoptosis and suppresses fatty acid β-oxidation under cisplatin-induced injury."},"narrative":{"mechanistic_narrative":"SLC38A6 (SNAT6) is a sodium-dependent glutamine and glutamate transporter that links amino acid transport to glutamatergic neurotransmission, tumor metabolism, and inflammatory and injury responses [PMID:33503881, PMID:35901507]. In the brain it is expressed selectively in excitatory neurons and localizes to synaptic membranes [PMID:24752331], where it resides at caveolin-rich plasma membrane sites and undergoes substrate- and sodium-dependent internalization through formation of SNAT6-caveolin complexes [PMID:33503881]. At the presynaptic terminal it associates with phosphate-activated glutaminase, synaptophysin, CTP synthase 2, and metabotropic glutamate receptor 2, positioning it within the glutamate-glutamine cycle by cycling between cytoplasm and plasma membrane according to substrate availability [PMID:33503881]. Beyond the synapse, SLC38A6 supports glutamine metabolism and mitochondrial respiration in hepatocellular carcinoma cells, where its expression is driven by promoter H3K27 acetylation laid down by EP300 [PMID:35901507] and by a ZNF652-circRHOT1-KAT5 axis that increases promoter H3K27ac to promote proliferation and suppress apoptosis [PMID:41311269]. In macrophages it acts downstream of TLR4 signaling to promote pro-inflammatory cytokine production [PMID:36707853], and in renal tubular cells it promotes apoptosis and suppresses fatty acid β-oxidation during cisplatin-induced acute kidney injury [PMID:41885504].","teleology":[{"year":2014,"claim":"Establishing where SNAT6 acts in the brain narrowed its physiological context from an orphan transporter to a candidate synaptic protein.","evidence":"Immunohistochemistry and proximity ligation assay with synaptic markers in mouse brain","pmids":["24752331"],"confidence":"Medium","gaps":["Transport substrates and activity not yet demonstrated","No functional consequence of synaptic localization tested"]},{"year":2021,"claim":"Identifying SNAT6 as a sodium-dependent glutamine/glutamate transporter that internalizes via caveolin complexes defined both its biochemical activity and a regulated trafficking mechanism.","evidence":"Tritium-labeled amino acid uptake assays, homology modeling, and co-IP/PLA for SNAT6-caveolin interaction","pmids":["33503881"],"confidence":"Medium","gaps":["Transport kinetics and stoichiometry not fully quantified","Caveolin interaction shown by indirect PLA/co-IP without structural detail"]},{"year":2021,"claim":"Mapping presynaptic interaction partners placed SNAT6 mechanistically within the glutamate-glutamine cycle.","evidence":"Co-expression, co-localization, and PLA for Pag, synaptophysin, CTPs2, and Grm2 at presynaptic terminals","pmids":["33503881"],"confidence":"Medium","gaps":["Interactions inferred from indirect proximity methods, not direct binding","Functional flux through the cycle not measured"]},{"year":2022,"claim":"Linking EP300-mediated promoter H3K27ac to SLC38A6 expression connected transporter levels to glutamine metabolism and mitochondrial respiration in cancer.","evidence":"ChIP, EP300 silencing, siRNA knockdown, and metabolic assays in hepatocellular carcinoma cells","pmids":["35901507"],"confidence":"Medium","gaps":["Direct transport contribution to the metabolic phenotype not isolated","In vivo tumor relevance not tested"]},{"year":2023,"claim":"Genetic and pharmacological epistasis placed SLC38A6 downstream of TLR4 and upstream of pro-inflammatory cytokine production in macrophages.","evidence":"Conditional and systemic knockout mice, TLR4 inhibitor and knockout, flow cytometry, and cytokine measurement in pulmonary inflammation models","pmids":["36707853"],"confidence":"Medium","gaps":["Molecular mechanism linking transport activity to cytokine production unresolved","Whether glutamine/glutamate flux drives the inflammatory phenotype not directly shown"]},{"year":2025,"claim":"A ZNF652-circRHOT1-KAT5 axis was defined as an additional epigenetic route activating SLC38A6 to promote HCC proliferation, extending the transcriptional regulatory picture.","evidence":"ChIP for H3K27ac/KAT5 occupancy, knockdown, overexpression rescue, and luciferase/binding assays in HCC cells","pmids":["41311269"],"confidence":"Medium","gaps":["Relationship between this axis and EP300-mediated regulation not integrated","Transport-dependence of proliferative effect not separated from regulatory effect"]},{"year":2026,"claim":"Tubular-specific knockout established SLC38A6 as a context-specific promoter of apoptosis and suppressor of fatty acid β-oxidation in cisplatin-induced acute kidney injury.","evidence":"KspCre conditional knockout mice, HK-2 knockdown, transcriptome sequencing, lipid and FAO enzyme assays, and TUNEL staining","pmids":["41885504"],"confidence":"High","gaps":["Mechanism connecting transport activity to FAO suppression unresolved","Whether the effect is specific to cisplatin injury or generalizes to other AKI models untested"]},{"year":null,"claim":"How SLC38A6's core transport activity mechanistically drives its divergent roles across synapse, tumor, macrophage, and kidney remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate binding and translocation","No direct demonstration that transport flux (versus protein presence) mediates the inflammatory and renal phenotypes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[1]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]}],"complexes":[],"partners":["CAV1","PAG","SYP","CTPS2","GRM2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IZM9","full_name":"Solute carrier family 38 member 6","aliases":["Amino acid transporter SLC38A6","N-system amino acid transporter 1","NAT-1"],"length_aa":456,"mass_kda":50.9,"function":"Amino acid transporter with an apparent selectivity for L-glutamine and L-glutamate. May facilitate glutamine uptake in excitatory neurons. The transport mechanism remains to be elucidated","subcellular_location":"Cell membrane; Synapse","url":"https://www.uniprot.org/uniprotkb/Q8IZM9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC38A6","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC38A6","total_profiled":1310},"omim":[{"mim_id":"616526","title":"SOLUTE CARRIER FAMILY 38 (AMINO ACID TRANSPORTER), MEMBER 11; SLC38A11","url":"https://www.omim.org/entry/616526"},{"mim_id":"616518","title":"SOLUTE CARRIER FAMILY 38 (AMINO ACID TRANSPORTER), MEMBER 6; SLC38A6","url":"https://www.omim.org/entry/616518"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cell Junctions","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Microtubules","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLC38A6"},"hgnc":{"alias_symbol":["NAT-1","SNAT6"],"prev_symbol":[]},"alphafold":{"accession":"Q8IZM9","domains":[{"cath_id":"1.20.1740.10","chopping":"48-218_243-456","consensus_level":"high","plddt":91.6485,"start":48,"end":456}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZM9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZM9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZM9-F1-predicted_aligned_error_v6.png","plddt_mean":84.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC38A6","jax_strain_url":"https://www.jax.org/strain/search?query=SLC38A6"},"sequence":{"accession":"Q8IZM9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IZM9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IZM9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZM9"}},"corpus_meta":[{"pmid":"1513324","id":"PMC_1513324","title":"Cloned mouse N-acetyltransferases: enzymatic properties of expressed Nat-1 and Nat-2 gene products.","date":"1992","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/1513324","citation_count":62,"is_preprint":false},{"pmid":"19123156","id":"PMC_19123156","title":"Nutritional AMD treatment phase I (NAT-1): feasibility of oral DHA supplementation in age-related macular degeneration.","date":"2009","source":"European journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/19123156","citation_count":27,"is_preprint":false},{"pmid":"33503881","id":"PMC_33503881","title":"Glutamine Uptake via SNAT6 and Caveolin Regulates Glutamine-Glutamate Cycle.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33503881","citation_count":22,"is_preprint":false},{"pmid":"16857729","id":"PMC_16857729","title":"N-acetyltransferase (Nat) 1 and 2 expression in Nat2 knockout mice.","date":"2006","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/16857729","citation_count":20,"is_preprint":false},{"pmid":"24752331","id":"PMC_24752331","title":"Histological analysis of SLC38A6 (SNAT6) expression in mouse brain shows selective expression in excitatory neurons with high expression in the synapses.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24752331","citation_count":18,"is_preprint":false},{"pmid":"9916872","id":"PMC_9916872","title":"Novel translational repressor (NAT-1) expression is modified by thyroid state and age in brain and liver.","date":"1998","source":"European journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/9916872","citation_count":13,"is_preprint":false},{"pmid":"35901507","id":"PMC_35901507","title":"SLC38A6, regulated by EP300-mediated modifications of H3K27ac, promotes cell proliferation, glutamine metabolism and mitochondrial respiration in hepatocellular carcinoma.","date":"2022","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/35901507","citation_count":12,"is_preprint":false},{"pmid":"35813866","id":"PMC_35813866","title":"Circ_0110940 Exerts an Antiapoptotic and Pro-Proliferative Effect in Gastric Cancer Cells via the miR-1178-3p/SLC38A6 Axis.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35813866","citation_count":10,"is_preprint":false},{"pmid":"36707853","id":"PMC_36707853","title":"SLC38A6 expression in macrophages exacerbates pulmonary inflammation.","date":"2023","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/36707853","citation_count":7,"is_preprint":false},{"pmid":"34773126","id":"PMC_34773126","title":"Investigations on detoxification mechanisms of novel para-phenylenediamine analogues through N-acetyltransferase 1 (NAT-1).","date":"2021","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/34773126","citation_count":2,"is_preprint":false},{"pmid":"39199395","id":"PMC_39199395","title":"Mouse Exploratory Behaviour in the Open Field with and without NAT-1 EEG Device: Effects of MK801 and Scopolamine.","date":"2024","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39199395","citation_count":2,"is_preprint":false},{"pmid":"41311269","id":"PMC_41311269","title":"Role of ZNF652 in Regulating Hepatocellular Carcinoma Cell Proliferation and Apoptosis via the circRHOT1/SLC38A6 Axis.","date":"2025","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41311269","citation_count":0,"is_preprint":false},{"pmid":"41885504","id":"PMC_41885504","title":"SLC38A6 expression in renal tubular cells accelerates cisplatin-induced acute kidney injury by promoting cell apoptosis.","date":"2026","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/41885504","citation_count":0,"is_preprint":false},{"pmid":"41344065","id":"PMC_41344065","title":"N-acetyltransferase (NAT) 1 and NAT2 enzyme activities drive interindividual variability in sulfamethoxazole N-acetylation.","date":"2025","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/41344065","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10149,"output_tokens":2493,"usd":0.033921,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9019,"output_tokens":2614,"usd":0.055223,"stage2_stop_reason":"end_turn"},"total_usd":0.089144,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"I need to classify each paper carefully. The query gene is SLC38A6 (also known as SNAT6). The alias \"NAT-1\" in the HGNC list refers to SLC38A6/SNAT6 — a solute carrier/amino acid transporter in neurons.\n\nHowever, several papers use \"NAT-1\" to refer to N-acetyltransferase 1 (a completely different gene/protein). I need to distinguish:\n- Papers about SLC38A6/SNAT6 (the solute carrier): Papers [3], [5], [7], [8], [9], [12], [13]\n- Papers about mouse N-acetyltransferase Nat-1: Papers [1], [4], [10], [14] — these are about a different protein (arylamine N-acetyltransferase), not SLC38A6\n- Paper [6]: \"NAT-1 translational repressor\" — this appears to be yet another different protein (eIF4G homolog/translational repressor), not SLC38A6\n- Paper [2]: NAT-1 = Nutritional AMD Treatment phase 1 trial — irrelevant\n- Paper [11]: NAT-1 = Neural Activity Tracker-1 device — irrelevant\n\nSo only papers [3], [5], [7], [8], [9], [12], [13] are about SLC38A6/SNAT6.\n\nPaper [8] is about circ_0110940/miR-1178-3p/SLC38A6 axis — a circRNA study. The SLC38A6 protein itself is being used as a downstream target but the mechanistic finding is about circRNA regulation. This is borderline but does establish a regulatory mechanism for SLC38A6 expression.\n\nPaper [12] is about circRHOT1/SLC38A6 — again circRNA study but establishes epigenetic regulation of SLC38A6 via KAT5/H3K27ac.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"SLC38A6 (SNAT6) is expressed selectively in excitatory neurons (not astrocytes) of the mouse brain and localizes to synaptic membranes, as established by immunohistochemistry and proximity ligation assay with proteins of known synaptic localization.\",\n      \"method\": \"Immunohistochemistry; proximity ligation assay (PLA) with synaptic marker proteins\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by IHC and PLA with functional context (synaptic membrane), single lab, two orthogonal methods\",\n      \"pmids\": [\"24752331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNAT6/SLC38A6 functions as a glutamine and glutamate transporter (demonstrated by tritium-labeled amino acid uptake assays), localizes to caveolin-rich sites at the plasma membrane, and undergoes substrate-dependent (glutamine/glutamate-triggered), sodium-dependent internalization via formation of SNAT6-caveolin complexes.\",\n      \"method\": \"Tritium-labeled amino acid transport assay; homology modeling (7 predicted TM segments); co-immunoprecipitation/proximity ligation assay for SNAT6-caveolin interaction; immunolabeling and co-localization analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transport assay with radiolabeled substrates plus PLA/co-IP for complex formation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33503881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNAT6/SLC38A6 interacts with phosphate-activated glutaminase (Pag), synaptophysin, CTP synthase 2 (CTPs2), and metabotropic glutamate receptor 2 (Grm2) at the pre-synaptic terminal, suggesting it participates in the glutamate-glutamine cycle by cycling between cytoplasm and plasma membrane depending on substrate availability.\",\n      \"method\": \"Co-expression analysis; immunolabeling with co-localization analysis; proximity ligation assay (PLA)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — PLA and co-localization are indirect interaction methods, single lab, multiple targets tested\",\n      \"pmids\": [\"33503881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SLC38A6 expression in hepatocellular carcinoma cells is regulated epigenetically: EP300 histone acetyltransferase mediates H3K27 acetylation at the SLC38A6 promoter, and silencing EP300 reduces H3K27ac occupancy at the promoter and decreases SLC38A6 expression. SLC38A6 knockdown inhibits glutamine metabolism and mitochondrial respiration in HCC cells.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) assay; luminescence assay for EP300-SLC38A6 interaction; siRNA knockdown; metabolic assays (glutamine metabolism, mitochondrial respiration)\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional validation by KD/OE, single lab, two orthogonal methods\",\n      \"pmids\": [\"35901507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLC38A6 expression in macrophages is upregulated downstream of TLR4 signaling: blocking TLR4 with TAK242 or Tlr4 knockout reduces Slc38a6 expression in macrophages. Conversely, Slc38a6 knockout (systemic or macrophage-specific via LyzCre) reduces pro-inflammatory cytokine expression (TNF-α, IL-1β) and monocyte numbers in pulmonary inflammation models, placing SLC38A6 downstream of TLR4 and upstream of IL-1β production.\",\n      \"method\": \"Conditional (LyzCRE) and systemic knockout mice; TLR4 inhibitor (TAK242); TLR4 knockout macrophages; flow cytometry; cytokine measurement (ELISA/qPCR); LPS-induced sepsis model\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via conditional KO plus pharmacological inhibition in two orthogonal models, single lab\",\n      \"pmids\": [\"36707853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZNF652 transcriptionally activates circRHOT1, which in turn recruits KAT5 histone acetyltransferase to the SLC38A6 promoter, increasing H3K27ac enrichment and activating SLC38A6 expression, thereby promoting HCC cell proliferation and inhibiting apoptosis.\",\n      \"method\": \"ChIP assay (H3K27ac, KAT5 occupancy at SLC38A6 promoter); siRNA knockdown; overexpression rescue experiments; luciferase/binding assays for ZNF652-circRHOT1 promoter interaction\",\n      \"journal\": \"The Kaohsiung journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for epigenetic regulation combined with rescue experiments, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41311269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SLC38A6 deficiency in renal tubular cells alleviates cisplatin-induced acute kidney injury by decreasing tubular cell apoptosis and promoting fatty acid β-oxidation (FAO): tubular-specific Slc38a6 knockout mice show reduced lipid deposition and increased expression of key FAO enzymes, placing SLC38A6 as a suppressor of FAO and promoter of apoptosis in this context.\",\n      \"method\": \"Conditional tubular-specific knockout (Slc38a6fl/fl × KspCre); siRNA knockdown in HK-2 cells; transcriptome sequencing; Oil Red O staining (lipid deposition); Western blot and RT-qPCR for FAO enzymes; TUNEL staining; renal function assays (BUN, creatinine)\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific conditional KO with transcriptome sequencing, validated in parallel in human cell line KD, multiple orthogonal readouts\",\n      \"pmids\": [\"41885504\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC38A6 (SNAT6) is a glutamine/glutamate transporter expressed at excitatory neuronal synapses that cycles between the plasma membrane and cytoplasm in a substrate- and sodium-dependent manner via caveolin complexes, participates in the glutamate-glutamine cycle through interactions with Pag, synaptophysin, CTPs2, and Grm2, is transcriptionally regulated by EP300-mediated H3K27ac and by the ZNF652-circRHOT1-KAT5 axis, acts downstream of TLR4 signaling in macrophages to promote pro-inflammatory cytokine production, and in renal tubular cells promotes apoptosis and suppresses fatty acid β-oxidation under cisplatin-induced injury.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC38A6 (SNAT6) is a sodium-dependent glutamine and glutamate transporter that links amino acid transport to glutamatergic neurotransmission, tumor metabolism, and inflammatory and injury responses [#1, #3]. In the brain it is expressed selectively in excitatory neurons and localizes to synaptic membranes [#0], where it resides at caveolin-rich plasma membrane sites and undergoes substrate- and sodium-dependent internalization through formation of SNAT6-caveolin complexes [#1]. At the presynaptic terminal it associates with phosphate-activated glutaminase, synaptophysin, CTP synthase 2, and metabotropic glutamate receptor 2, positioning it within the glutamate-glutamine cycle by cycling between cytoplasm and plasma membrane according to substrate availability [#2]. Beyond the synapse, SLC38A6 supports glutamine metabolism and mitochondrial respiration in hepatocellular carcinoma cells, where its expression is driven by promoter H3K27 acetylation laid down by EP300 [#3] and by a ZNF652-circRHOT1-KAT5 axis that increases promoter H3K27ac to promote proliferation and suppress apoptosis [#5]. In macrophages it acts downstream of TLR4 signaling to promote pro-inflammatory cytokine production [#4], and in renal tubular cells it promotes apoptosis and suppresses fatty acid \\u03b2-oxidation during cisplatin-induced acute kidney injury [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing where SNAT6 acts in the brain narrowed its physiological context from an orphan transporter to a candidate synaptic protein.\",\n      \"evidence\": \"Immunohistochemistry and proximity ligation assay with synaptic markers in mouse brain\",\n      \"pmids\": [\"24752331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transport substrates and activity not yet demonstrated\", \"No functional consequence of synaptic localization tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying SNAT6 as a sodium-dependent glutamine/glutamate transporter that internalizes via caveolin complexes defined both its biochemical activity and a regulated trafficking mechanism.\",\n      \"evidence\": \"Tritium-labeled amino acid uptake assays, homology modeling, and co-IP/PLA for SNAT6-caveolin interaction\",\n      \"pmids\": [\"33503881\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transport kinetics and stoichiometry not fully quantified\", \"Caveolin interaction shown by indirect PLA/co-IP without structural detail\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapping presynaptic interaction partners placed SNAT6 mechanistically within the glutamate-glutamine cycle.\",\n      \"evidence\": \"Co-expression, co-localization, and PLA for Pag, synaptophysin, CTPs2, and Grm2 at presynaptic terminals\",\n      \"pmids\": [\"33503881\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interactions inferred from indirect proximity methods, not direct binding\", \"Functional flux through the cycle not measured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linking EP300-mediated promoter H3K27ac to SLC38A6 expression connected transporter levels to glutamine metabolism and mitochondrial respiration in cancer.\",\n      \"evidence\": \"ChIP, EP300 silencing, siRNA knockdown, and metabolic assays in hepatocellular carcinoma cells\",\n      \"pmids\": [\"35901507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transport contribution to the metabolic phenotype not isolated\", \"In vivo tumor relevance not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Genetic and pharmacological epistasis placed SLC38A6 downstream of TLR4 and upstream of pro-inflammatory cytokine production in macrophages.\",\n      \"evidence\": \"Conditional and systemic knockout mice, TLR4 inhibitor and knockout, flow cytometry, and cytokine measurement in pulmonary inflammation models\",\n      \"pmids\": [\"36707853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking transport activity to cytokine production unresolved\", \"Whether glutamine/glutamate flux drives the inflammatory phenotype not directly shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A ZNF652-circRHOT1-KAT5 axis was defined as an additional epigenetic route activating SLC38A6 to promote HCC proliferation, extending the transcriptional regulatory picture.\",\n      \"evidence\": \"ChIP for H3K27ac/KAT5 occupancy, knockdown, overexpression rescue, and luciferase/binding assays in HCC cells\",\n      \"pmids\": [\"41311269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between this axis and EP300-mediated regulation not integrated\", \"Transport-dependence of proliferative effect not separated from regulatory effect\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Tubular-specific knockout established SLC38A6 as a context-specific promoter of apoptosis and suppressor of fatty acid \\u03b2-oxidation in cisplatin-induced acute kidney injury.\",\n      \"evidence\": \"KspCre conditional knockout mice, HK-2 knockdown, transcriptome sequencing, lipid and FAO enzyme assays, and TUNEL staining\",\n      \"pmids\": [\"41885504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting transport activity to FAO suppression unresolved\", \"Whether the effect is specific to cisplatin injury or generalizes to other AKI models untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SLC38A6's core transport activity mechanistically drives its divergent roles across synapse, tumor, macrophage, and kidney remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate binding and translocation\", \"No direct demonstration that transport flux (versus protein presence) mediates the inflammatory and renal phenotypes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CAV1\", \"PAG\", \"SYP\", \"CTPS2\", \"GRM2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}