{"gene":"SOAT1","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2020,"finding":"SOAT1 (sterol O-acyltransferase 1) sustains the mevalonate pathway by converting free cholesterol to inert cholesterol esters, thereby preventing the negative feedback inhibition elicited by unesterified cholesterol accumulation. Genetic targeting of Soat1 impairs cell proliferation in vitro and tumor progression in vivo, and reveals a mevalonate pathway dependency specifically in p53 mutant PDAC cells that have undergone p53 loss of heterozygosity (LOH); pancreatic organoids lacking p53 mutation and p53 LOH are insensitive to SOAT1 loss.","method":"Genetic knockout/knockdown in organoid and mouse models; in vitro proliferation assays; in vivo tumor progression assays; genetic epistasis with p53 LOH status","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined cellular and in vivo phenotype, multiple orthogonal models (organoids + mouse), epistasis with p53 LOH establishing pathway position","pmids":["32633781"],"is_preprint":false},{"year":2021,"finding":"SOAT1 promotes gastric cancer lymph node metastasis by driving cholesterol ester synthesis. Mechanistically, SOAT1 regulates expression of cholesterol metabolism genes SREBP1 and SREBP2, which in turn induces lymphangiogenesis by increasing VEGF-C expression. Knockdown or pharmacological inhibition of SOAT1 by avasimibe suppresses cell proliferation, cholesterol ester synthesis, and lymphangiogenesis; overexpression promotes these processes.","method":"siRNA knockdown; pharmacological inhibition (avasimibe); overexpression; cholesterol ester synthesis assays; lymphangiogenesis assays; western blot for SREBP1, SREBP2, VEGF-C","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple orthogonal methods (KD, OE, pharmacological inhibition) with defined mechanistic pathway (SOAT1→SREBP1/2→VEGF-C→lymphangiogenesis)","pmids":["34790132"],"is_preprint":false},{"year":2021,"finding":"SOAT1 inhibition (by avasimibe) enhances CPT1A protein levels, shuttling released fatty acids into mitochondria for oxidation. Conversely, CPT1A inhibition causes excess fatty acids to be converted into lipid droplets via SOAT1. These two enzymes form a double-negative feedback loop regulating lipid homeostasis in HCC. Simultaneous targeting of SOAT1 and CPT1A with avasimibe and etomoxir produces synergistic anticancer efficacy in HCC in vitro and in vivo.","method":"Pharmacological inhibition (avasimibe, etomoxir); in vitro and in vivo HCC models; western blot; lipid droplet quantification; bioinformatic analysis of feedback loop","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple orthogonal methods (pharmacological inhibition in vitro and in vivo), defined mechanistic feedback loop between SOAT1 and CPT1A","pmids":["34052835"],"is_preprint":false},{"year":2024,"finding":"SOAT1 promotes epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma by increasing cholesterol esterification, which elevates cholesterol in the plasma membrane and accumulates cholesterol esters. The natural compound nootkatone inhibits SOAT1 activity, thereby suppressing EMT both in vitro and in vivo.","method":"SOAT1 overexpression and knockdown; cholesterol esterification assays; plasma membrane cholesterol measurement; EMT marker analysis; xenograft and NAFLD-HCC mouse models; pharmacological inhibition with nootkatone","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple orthogonal approaches (genetic manipulation + pharmacological inhibition + in vivo models) linking SOAT1-mediated cholesterol esterification to EMT","pmids":["38724499"],"is_preprint":false}],"current_model":"SOAT1 (sterol O-acyltransferase 1) is an ER-resident enzyme that esterifies free cholesterol to cholesterol esters, thereby preventing cholesterol-mediated negative feedback on the mevalonate pathway; in cancer contexts this sustains mevalonate pathway activity, promotes cell proliferation and tumor progression (particularly in p53-mutant/LOH settings), drives SREBP1/2-mediated VEGF-C upregulation and lymphangiogenesis, participates in a double-negative feedback loop with CPT1A to regulate fatty acid/lipid homeostasis, and facilitates epithelial-mesenchymal transition through plasma membrane cholesterol enrichment and cholesterol ester accumulation."},"narrative":{"mechanistic_narrative":"SOAT1 (sterol O-acyltransferase 1) esterifies free cholesterol into inert cholesterol esters, a reaction that prevents unesterified cholesterol from exerting negative feedback on the mevalonate pathway and thereby sustains its flux [PMID:32633781]. Through this activity SOAT1 supports cell proliferation and tumor progression, with a selective dependency in p53-mutant pancreatic cancer cells that have undergone p53 loss of heterozygosity, while p53-wild-type organoids are insensitive to its loss [PMID:32633781]. Beyond maintaining mevalonate output, SOAT1-driven cholesterol ester synthesis feeds into downstream programs: it regulates the cholesterol metabolism regulators SREBP1 and SREBP2 to upregulate VEGF-C and drive lymphangiogenesis and lymph node metastasis in gastric cancer [PMID:34790132], it elevates plasma membrane cholesterol and cholesterol ester accumulation to promote epithelial-mesenchymal transition in hepatocellular carcinoma [PMID:38724499], and it participates in a double-negative feedback loop with CPT1A that partitions fatty acids between lipid droplet storage and mitochondrial oxidation [PMID:34052835]. Pharmacological inhibition of SOAT1 (avasimibe, nootkatone) suppresses these oncogenic outputs, and co-targeting SOAT1 and CPT1A produces synergistic anticancer effects [PMID:34790132, PMID:34052835, PMID:38724499].","teleology":[{"year":2020,"claim":"Established the core mechanistic logic by which SOAT1 supports tumor growth: cholesterol esterification relieves feedback inhibition of the mevalonate pathway, creating a context-specific dependency tied to p53 status.","evidence":"Genetic knockout/knockdown in organoid and mouse PDAC models with in vitro proliferation and in vivo tumor assays, epistasis with p53 LOH","pmids":["32633781"],"confidence":"High","gaps":["Does not define the molecular sensor linking cholesterol ester levels to mevalonate pathway feedback","Mechanism by which p53 LOH specifically confers SOAT1 dependency not resolved","No structural or enzymatic characterization of SOAT1 in this context"]},{"year":2021,"claim":"Connected SOAT1's cholesterol ester output to a transcriptional and angiogenic program, showing it acts through SREBP1/2 to induce VEGF-C and lymphangiogenesis driving metastasis.","evidence":"siRNA knockdown, overexpression, avasimibe inhibition, cholesterol ester and lymphangiogenesis assays, and western blot in gastric cancer","pmids":["34790132"],"confidence":"Medium","gaps":["Mechanism linking cholesterol ester synthesis to SREBP1/2 regulation not defined","Single-lab findings without reciprocal validation","Direct interaction between SOAT1 and the SREBP machinery not established"]},{"year":2021,"claim":"Defined SOAT1's role in lipid partitioning, revealing a double-negative feedback loop with CPT1A that balances fatty acid storage versus oxidation and exposing a synthetic-lethal co-targeting strategy.","evidence":"Pharmacological inhibition with avasimibe and etomoxir in vitro and in vivo HCC models, western blot, lipid droplet quantification, bioinformatic analysis","pmids":["34052835"],"confidence":"Medium","gaps":["Molecular basis of the reciprocal SOAT1–CPT1A regulation not mechanistically dissected","Single-lab study relying largely on pharmacological inhibitors","Direct physical interaction between SOAT1 and CPT1A not demonstrated"]},{"year":2024,"claim":"Linked SOAT1 cholesterol esterification to membrane remodeling, showing that plasma membrane cholesterol enrichment and cholesterol ester accumulation drive EMT in HCC.","evidence":"SOAT1 overexpression/knockdown, cholesterol esterification and plasma membrane cholesterol assays, EMT marker analysis, xenograft and NAFLD-HCC models, nootkatone inhibition","pmids":["38724499"],"confidence":"Medium","gaps":["Mechanism connecting plasma membrane cholesterol to EMT signaling not defined","Single-lab findings with inhibitor specificity not orthogonally confirmed","Whether EMT effect is shared across cancer types untested"]},{"year":null,"claim":"How SOAT1's single enzymatic activity is mechanistically routed into distinct downstream programs (mevalonate feedback, SREBP/VEGF-C transcription, CPT1A lipid partitioning, membrane EMT) across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying molecular model linking cholesterol esterification to its multiple downstream effects","Structural and enzymatic mechanism of SOAT1 not addressed in the corpus","Regulatory inputs controlling SOAT1 activity not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,3]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35610","full_name":"Sterol O-acyltransferase 1","aliases":["Acyl-coenzyme A:cholesterol acyltransferase 1","ACAT-1","Cholesterol acyltransferase 1"],"length_aa":550,"mass_kda":64.7,"function":"Catalyzes the formation of fatty acid-cholesterol esters, which are less soluble in membranes than cholesterol (PubMed:16154994, PubMed:16647063, PubMed:32433613, PubMed:32433614, PubMed:32944968, PubMed:9020103). Plays a role in lipoprotein assembly and dietary cholesterol absorption (PubMed:16154994, PubMed:9020103). Preferentially utilizes oleoyl-CoA ((9Z)-octadecenoyl-CoA) as a substrate: shows a higher activity towards an acyl-CoA substrate with a double bond at the delta-9 position (9Z) than towards saturated acyl-CoA or an unsaturated acyl-CoA with a double bond at the delta-7 (7Z) or delta-11 (11Z) positions (PubMed:11294643, PubMed:32433614)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P35610/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SOAT1","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":[{"gene":"VAPA","stoichiometry":0.2},{"gene":"VAPB","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SOAT1","total_profiled":1310},"omim":[{"mim_id":"611632","title":"UbiA PRENYLTRANSFERASE DOMAIN-CONTAINING PROTEIN 1; UBIAD1","url":"https://www.omim.org/entry/611632"},{"mim_id":"601311","title":"STEROL O-ACYLTRANSFERASE 2; SOAT2","url":"https://www.omim.org/entry/601311"},{"mim_id":"114835","title":"CARBOXYLESTERASE 1; CES1","url":"https://www.omim.org/entry/114835"},{"mim_id":"114550","title":"HEPATOCELLULAR CARCINOMA","url":"https://www.omim.org/entry/114550"},{"mim_id":"104760","title":"AMYLOID BETA A4 PRECURSOR PROTEIN; APP","url":"https://www.omim.org/entry/104760"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Endoplasmic reticulum","reliability":"Enhanced"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adrenal gland","ntpm":155.9}],"url":"https://www.proteinatlas.org/search/SOAT1"},"hgnc":{"alias_symbol":["ACAT","ACAT1"],"prev_symbol":["SOAT","STAT"]},"alphafold":{"accession":"P35610","domains":[{"cath_id":"-","chopping":"118-169_312-403","consensus_level":"medium","plddt":90.5993,"start":118,"end":403},{"cath_id":"-","chopping":"171-302","consensus_level":"medium","plddt":92.9899,"start":171,"end":302},{"cath_id":"-","chopping":"410-550","consensus_level":"medium","plddt":85.2801,"start":410,"end":550}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35610","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35610-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35610-F1-predicted_aligned_error_v6.png","plddt_mean":80.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SOAT1","jax_strain_url":"https://www.jax.org/strain/search?query=SOAT1"},"sequence":{"accession":"P35610","fasta_url":"https://rest.uniprot.org/uniprotkb/P35610.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35610/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35610"}},"corpus_meta":[{"pmid":"34824210","id":"PMC_34824210","title":"The 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O-acyltransferase 1) sustains the mevalonate pathway by converting free cholesterol to inert cholesterol esters, thereby preventing the negative feedback inhibition elicited by unesterified cholesterol accumulation. Genetic targeting of Soat1 impairs cell proliferation in vitro and tumor progression in vivo, and reveals a mevalonate pathway dependency specifically in p53 mutant PDAC cells that have undergone p53 loss of heterozygosity (LOH); pancreatic organoids lacking p53 mutation and p53 LOH are insensitive to SOAT1 loss.\",\n      \"method\": \"Genetic knockout/knockdown in organoid and mouse models; in vitro proliferation assays; in vivo tumor progression assays; genetic epistasis with p53 LOH status\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined cellular and in vivo phenotype, multiple orthogonal models (organoids + mouse), epistasis with p53 LOH establishing pathway position\",\n      \"pmids\": [\"32633781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SOAT1 promotes gastric cancer lymph node metastasis by driving cholesterol ester synthesis. Mechanistically, SOAT1 regulates expression of cholesterol metabolism genes SREBP1 and SREBP2, which in turn induces lymphangiogenesis by increasing VEGF-C expression. Knockdown or pharmacological inhibition of SOAT1 by avasimibe suppresses cell proliferation, cholesterol ester synthesis, and lymphangiogenesis; overexpression promotes these processes.\",\n      \"method\": \"siRNA knockdown; pharmacological inhibition (avasimibe); overexpression; cholesterol ester synthesis assays; lymphangiogenesis assays; western blot for SREBP1, SREBP2, VEGF-C\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple orthogonal methods (KD, OE, pharmacological inhibition) with defined mechanistic pathway (SOAT1→SREBP1/2→VEGF-C→lymphangiogenesis)\",\n      \"pmids\": [\"34790132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SOAT1 inhibition (by avasimibe) enhances CPT1A protein levels, shuttling released fatty acids into mitochondria for oxidation. Conversely, CPT1A inhibition causes excess fatty acids to be converted into lipid droplets via SOAT1. These two enzymes form a double-negative feedback loop regulating lipid homeostasis in HCC. Simultaneous targeting of SOAT1 and CPT1A with avasimibe and etomoxir produces synergistic anticancer efficacy in HCC in vitro and in vivo.\",\n      \"method\": \"Pharmacological inhibition (avasimibe, etomoxir); in vitro and in vivo HCC models; western blot; lipid droplet quantification; bioinformatic analysis of feedback loop\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple orthogonal methods (pharmacological inhibition in vitro and in vivo), defined mechanistic feedback loop between SOAT1 and CPT1A\",\n      \"pmids\": [\"34052835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SOAT1 promotes epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma by increasing cholesterol esterification, which elevates cholesterol in the plasma membrane and accumulates cholesterol esters. The natural compound nootkatone inhibits SOAT1 activity, thereby suppressing EMT both in vitro and in vivo.\",\n      \"method\": \"SOAT1 overexpression and knockdown; cholesterol esterification assays; plasma membrane cholesterol measurement; EMT marker analysis; xenograft and NAFLD-HCC mouse models; pharmacological inhibition with nootkatone\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple orthogonal approaches (genetic manipulation + pharmacological inhibition + in vivo models) linking SOAT1-mediated cholesterol esterification to EMT\",\n      \"pmids\": [\"38724499\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SOAT1 (sterol O-acyltransferase 1) is an ER-resident enzyme that esterifies free cholesterol to cholesterol esters, thereby preventing cholesterol-mediated negative feedback on the mevalonate pathway; in cancer contexts this sustains mevalonate pathway activity, promotes cell proliferation and tumor progression (particularly in p53-mutant/LOH settings), drives SREBP1/2-mediated VEGF-C upregulation and lymphangiogenesis, participates in a double-negative feedback loop with CPT1A to regulate fatty acid/lipid homeostasis, and facilitates epithelial-mesenchymal transition through plasma membrane cholesterol enrichment and cholesterol ester accumulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SOAT1 (sterol O-acyltransferase 1) esterifies free cholesterol into inert cholesterol esters, a reaction that prevents unesterified cholesterol from exerting negative feedback on the mevalonate pathway and thereby sustains its flux [#0]. Through this activity SOAT1 supports cell proliferation and tumor progression, with a selective dependency in p53-mutant pancreatic cancer cells that have undergone p53 loss of heterozygosity, while p53-wild-type organoids are insensitive to its loss [#0]. Beyond maintaining mevalonate output, SOAT1-driven cholesterol ester synthesis feeds into downstream programs: it regulates the cholesterol metabolism regulators SREBP1 and SREBP2 to upregulate VEGF-C and drive lymphangiogenesis and lymph node metastasis in gastric cancer [#1], it elevates plasma membrane cholesterol and cholesterol ester accumulation to promote epithelial-mesenchymal transition in hepatocellular carcinoma [#3], and it participates in a double-negative feedback loop with CPT1A that partitions fatty acids between lipid droplet storage and mitochondrial oxidation [#2]. Pharmacological inhibition of SOAT1 (avasimibe, nootkatone) suppresses these oncogenic outputs, and co-targeting SOAT1 and CPT1A produces synergistic anticancer effects [#1, #2, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Established the core mechanistic logic by which SOAT1 supports tumor growth: cholesterol esterification relieves feedback inhibition of the mevalonate pathway, creating a context-specific dependency tied to p53 status.\",\n      \"evidence\": \"Genetic knockout/knockdown in organoid and mouse PDAC models with in vitro proliferation and in vivo tumor assays, epistasis with p53 LOH\",\n      \"pmids\": [\"32633781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not define the molecular sensor linking cholesterol ester levels to mevalonate pathway feedback\",\n        \"Mechanism by which p53 LOH specifically confers SOAT1 dependency not resolved\",\n        \"No structural or enzymatic characterization of SOAT1 in this context\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected SOAT1's cholesterol ester output to a transcriptional and angiogenic program, showing it acts through SREBP1/2 to induce VEGF-C and lymphangiogenesis driving metastasis.\",\n      \"evidence\": \"siRNA knockdown, overexpression, avasimibe inhibition, cholesterol ester and lymphangiogenesis assays, and western blot in gastric cancer\",\n      \"pmids\": [\"34790132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking cholesterol ester synthesis to SREBP1/2 regulation not defined\",\n        \"Single-lab findings without reciprocal validation\",\n        \"Direct interaction between SOAT1 and the SREBP machinery not established\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined SOAT1's role in lipid partitioning, revealing a double-negative feedback loop with CPT1A that balances fatty acid storage versus oxidation and exposing a synthetic-lethal co-targeting strategy.\",\n      \"evidence\": \"Pharmacological inhibition with avasimibe and etomoxir in vitro and in vivo HCC models, western blot, lipid droplet quantification, bioinformatic analysis\",\n      \"pmids\": [\"34052835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular basis of the reciprocal SOAT1\\u2013CPT1A regulation not mechanistically dissected\",\n        \"Single-lab study relying largely on pharmacological inhibitors\",\n        \"Direct physical interaction between SOAT1 and CPT1A not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked SOAT1 cholesterol esterification to membrane remodeling, showing that plasma membrane cholesterol enrichment and cholesterol ester accumulation drive EMT in HCC.\",\n      \"evidence\": \"SOAT1 overexpression/knockdown, cholesterol esterification and plasma membrane cholesterol assays, EMT marker analysis, xenograft and NAFLD-HCC models, nootkatone inhibition\",\n      \"pmids\": [\"38724499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism connecting plasma membrane cholesterol to EMT signaling not defined\",\n        \"Single-lab findings with inhibitor specificity not orthogonally confirmed\",\n        \"Whether EMT effect is shared across cancer types untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SOAT1's single enzymatic activity is mechanistically routed into distinct downstream programs (mevalonate feedback, SREBP/VEGF-C transcription, CPT1A lipid partitioning, membrane EMT) across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unifying molecular model linking cholesterol esterification to its multiple downstream effects\",\n        \"Structural and enzymatic mechanism of SOAT1 not addressed in the corpus\",\n        \"Regulatory inputs controlling SOAT1 activity not characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}