{"gene":"MBOAT2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2024,"finding":"MBOAT2 overexpression disrupts glycerophospholipid metabolism and induces endothelial cell pyroptosis in an endoplasmic reticulum stress-dependent manner; genetic upregulation of MBOAT2 via AAV with endothelium-specific promoter increases atherosclerotic lesions in ApoE-/- mice, and TMAO promotes this pathway by upregulating MBOAT2 expression.","method":"AAV-mediated endothelium-specific MBOAT2 overexpression in ApoE-/- mice, lipidomic analysis of glycerophospholipid metabolism, ER stress assays, pyroptosis readouts","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function with defined phenotypic readout (atherosclerosis, pyroptosis) and mechanistic pathway (ER stress), single lab with multiple orthogonal methods","pmids":["39179098"],"is_preprint":false},{"year":2025,"finding":"FERMT1 physically interacts with MBOAT2 to suppress ferroptosis in glioma cells; depletion of MBOAT2 abolishes the anti-ferroptotic effects of FERMT1, and MBOAT2 overexpression rescues ferroptosis in FERMT1-deficient cells, defining a FERMT1-MBOAT2 axis that regulates ferroptosis.","method":"Co-immunoprecipitation (interaction), gain- and loss-of-function experiments, erastin-induced ferroptosis assay, ferrostatin-1 rescue","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined ferroptosis phenotype and rescue, single lab with multiple orthogonal methods","pmids":["41093166"],"is_preprint":false},{"year":2025,"finding":"MBOAT2 functions as a lysophospholipid acyltransferase that limits the incorporation of polyunsaturated fatty acids (PUFAs) into phosphatidylcholine (PC), thereby enriching monounsaturated fatty acids (MUFAs) in PC; this activity is highly induced in activated satellite cells and promotes muscle regeneration by buffering oxidative stress from lipid peroxidation.","method":"Lipidomic profiling, loss- and gain-of-function experiments in skeletal muscle/satellite cells, enzymatic characterization as lysophospholipid acyltransferase","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — enzymatic activity established with lipidomic profiling and loss/gain-of-function, but preprint (single lab, not yet peer-reviewed)","pmids":["bio_10.1101_2025.11.02.686003"],"is_preprint":true},{"year":2024,"finding":"In hypoxia-induced cognitive impairment, HBO therapy upregulates MBOAT2 and oleic acid, leading to membrane phospholipid remodeling; in vitro experiments confirmed that oleic acid and MBOAT2 act in a mutually dependent manner to remodel membrane phospholipids and reduce neuronal ferroptosis.","method":"In vivo hypoxia mouse model with HBO treatment, metabolomic/lipidomic analysis, in vitro cell experiments with MBOAT2 and oleic acid manipulation, molecular biology","journal":"Antioxidants (Basel, Switzerland)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic detail in abstract, mutual dependence of OA and MBOAT2 stated but not fully dissected","pmids":["39594462"],"is_preprint":false},{"year":2025,"finding":"AR (androgen receptor) acts as an upstream signaling molecule of MBOAT2; YB60 treatment increases AR and MBOAT2 expression in spinal cord neurons, and knockdown of AR eliminates YB60-induced upregulation of MBOAT2 and its anti-ferroptotic effects, placing MBOAT2 downstream of AR in a ferroptosis-regulatory pathway.","method":"Western blotting, immunofluorescent dual staining, AR knockdown in PC12 cells, erastin-induced ferroptosis model","journal":"Frontiers in pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single genetic manipulation (AR knockdown) with MBOAT2 readout, limited mechanistic depth","pmids":["40201699"],"is_preprint":false},{"year":2022,"finding":"MBOAT2 overexpression in pancreatic cancer cells accelerates cell proliferation and migration and enhances CDK2 and CCNA2 expression, promoting cell cycle progression from G1 to G2 phase.","method":"MTT, colony formation, Transwell assays, flow cytometry cell cycle analysis, western blot","journal":"Journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression with phenotypic readouts but limited mechanistic pathway dissection","pmids":["35571489"],"is_preprint":false}],"current_model":"MBOAT2 is a lysophospholipid acyltransferase that remodels membrane phosphatidylcholine by incorporating monounsaturated fatty acids at the expense of polyunsaturated fatty acids, thereby suppressing lipid peroxidation and ferroptosis; it operates downstream of androgen receptor signaling and physically interacts with FERMT1 to regulate ferroptosis in cancer cells, while its dysregulation in endothelial cells disrupts glycerophospholipid metabolism, induces ER stress-dependent pyroptosis, and promotes atherosclerosis."},"narrative":{"mechanistic_narrative":"MBOAT2 is a lysophospholipid acyltransferase that remodels membrane phospholipid composition by limiting the incorporation of polyunsaturated fatty acids into phosphatidylcholine while enriching monounsaturated fatty acids, an activity that buffers oxidative stress from lipid peroxidation and thereby suppresses ferroptosis [PMID:bio_10.1101_2025.11.02.686003]. Through this membrane-remodeling function it acts as a protective factor in multiple settings: its induction in activated satellite cells promotes muscle regeneration [PMID:bio_10.1101_2025.11.02.686003], and in neurons it cooperates with oleic acid in a mutually dependent manner to reduce ferroptosis [PMID:39594462]. The anti-ferroptotic activity of MBOAT2 is governed by upstream regulators and physical partners — androgen receptor signaling drives MBOAT2 expression to limit neuronal ferroptosis [PMID:40201699], and FERMT1 physically interacts with MBOAT2 to suppress ferroptosis, an effect that requires MBOAT2 and is restored by its overexpression in FERMT1-deficient cells [PMID:41093166]. In endothelial cells, gain of MBOAT2 disrupts glycerophospholipid metabolism and triggers endoplasmic reticulum stress-dependent pyroptosis, and endothelium-specific overexpression aggravates atherosclerosis in ApoE-/- mice, a pathway induced by TMAO [PMID:39179098]. MBOAT2 overexpression also accelerates proliferation, migration, and cell cycle progression in pancreatic cancer cells [PMID:35571489].","teleology":[{"year":2022,"claim":"An initial link between MBOAT2 and cancer cell behavior was established, showing that elevated MBOAT2 can drive proliferation and cell cycle progression.","evidence":"MBOAT2 overexpression with proliferation, migration, and flow cytometry cell-cycle assays in pancreatic cancer cells","pmids":["35571489"],"confidence":"Low","gaps":["Single overexpression study without mechanistic dissection of how MBOAT2 enzymatic activity drives CDK2/CCNA2 induction","No link to lipid remodeling or ferroptosis in this context","Loss-of-function not tested"]},{"year":2024,"claim":"MBOAT2 was implicated as a pathogenic effector in vascular disease, defining a context where its overexpression is harmful rather than protective.","evidence":"AAV endothelium-specific MBOAT2 overexpression in ApoE-/- mice with lipidomics, ER stress, and pyroptosis readouts","pmids":["39179098"],"confidence":"Medium","gaps":["Molecular link between glycerophospholipid disruption and ER stress not fully mapped","Direct enzymatic mechanism in endothelial cells not characterized","How TMAO upregulates MBOAT2 transcriptionally is unresolved"]},{"year":2024,"claim":"MBOAT2 was tied to neuronal protection through membrane phospholipid remodeling and a dependency on oleic acid.","evidence":"Hypoxia mouse model with HBO therapy, lipidomic analysis, and in vitro MBOAT2/oleic acid manipulation","pmids":["39594462"],"confidence":"Low","gaps":["Mutual dependence of oleic acid and MBOAT2 stated but not mechanistically dissected","Direct enzymatic assay not performed in this system","Single lab"]},{"year":2025,"claim":"The enzymatic identity of MBOAT2 as a lysophospholipid acyltransferase favoring MUFA over PUFA incorporation into PC was established, providing the biochemical basis for its anti-ferroptotic role.","evidence":"Lipidomic profiling and loss/gain-of-function in satellite cells with enzymatic characterization (preprint)","pmids":["bio_10.1101_2025.11.02.686003"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Substrate specificity and structural basis of acyl-chain selectivity not defined","Generalizability beyond muscle regeneration to be confirmed"]},{"year":2025,"claim":"Upstream and physical regulators of MBOAT2 in ferroptosis were identified, placing it downstream of androgen receptor and in complex with FERMT1.","evidence":"AR knockdown in PC12 cells and Co-IP plus reciprocal gain/loss-of-function with erastin/ferrostatin-1 ferroptosis assays in glioma cells","pmids":["40201699","41093166"],"confidence":"Medium","gaps":["Whether AR regulates MBOAT2 directly at the transcriptional level is unknown","FERMT1-MBOAT2 interaction interface and stoichiometry not defined","Single Co-IP without reciprocal/structural validation"]},{"year":null,"claim":"How MBOAT2's single acyltransferase activity produces opposite outcomes — protective anti-ferroptotic remodeling versus pathogenic glycerophospholipid disruption and pyroptosis — across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model reconciling protective versus pathogenic phenotypes","No structural data on substrate selectivity","Direct enzymatic kinetics not reported in peer-reviewed work"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0]}],"complexes":[],"partners":["FERMT1","AR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6ZWT7","full_name":"Membrane-bound glycerophospholipid O-acyltransferase 2","aliases":["1-acylglycerophosphate O-acyltransferase MBOAT2","1-acylglycerophosphocholine O-acyltransferase MBOAT2","1-acylglycerophosphoethanolamine MBOAT2 O-acyltransferase","Lysophosphatidic acid acyltransferase","LPAAT","Lyso-PA acyltransferase","Lysophosphatidylcholine acyltransferase","LPCAT","Lyso-PC acyltransferase","Lysophosphatidylcholine acyltransferase 4","Lyso-PC acyltransferase 4","Lysophosphatidylethanolamine acyltransferase","LPEAT","Lyso-PE acyltransferase","Lysophospholipid acyltransferase 2","LPLAT 2","Membrane-bound O-acyltransferase domain-containing protein 2","O-acyltransferase domain-containing protein 2"],"length_aa":520,"mass_kda":59.5,"function":"Acyltransferase which catalyzes the transfer of an acyl group from an acyl-CoA to a lysophospholipid leading to the production of a phospholipid and participates in the reacylation step of the phospholipid remodeling pathway also known as the Lands cycle (PubMed:18772128). Catalyzes preferentially the acylation of lysophosphatidylethanolamine (1-acyl-sn-glycero-3-phosphoethanolamine or LPE) and lysophosphatidic acid (LPA) and to a lesser extend lysophosphatidylcholine (LPC) and lysophosphatidylserine (LPS) (PubMed:18772128). Prefers oleoyl-CoA as the acyl donor (PubMed:18772128). May be involved in chondrocyte differentiation (By similarity)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q6ZWT7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MBOAT2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000143797","cell_line_id":"CID000337","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"er","grade":2}],"interactors":[{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000337","total_profiled":1310},"omim":[{"mim_id":"611949","title":"MEMBRANE-BOUND O-ACYLTRANSFERASE DOMAIN-CONTAINING PROTEIN 2; MBOAT2","url":"https://www.omim.org/entry/611949"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MBOAT2"},"hgnc":{"alias_symbol":["FLJ14415","FLJ90298","LPLAT13"],"prev_symbol":["OACT2"]},"alphafold":{"accession":"Q6ZWT7","domains":[{"cath_id":"-","chopping":"18-204","consensus_level":"high","plddt":93.9696,"start":18,"end":204},{"cath_id":"-","chopping":"228-323","consensus_level":"medium","plddt":94.5473,"start":228,"end":323},{"cath_id":"-","chopping":"325-467","consensus_level":"medium","plddt":95.2436,"start":325,"end":467}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZWT7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZWT7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZWT7-F1-predicted_aligned_error_v6.png","plddt_mean":86.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MBOAT2","jax_strain_url":"https://www.jax.org/strain/search?query=MBOAT2"},"sequence":{"accession":"Q6ZWT7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6ZWT7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6ZWT7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZWT7"}},"corpus_meta":[{"pmid":"33832516","id":"PMC_33832516","title":"Circ-MBOAT2 knockdown represses tumor progression and glutamine catabolism by miR-433-3p/GOT1 axis in pancreatic cancer.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33832516","citation_count":62,"is_preprint":false},{"pmid":"36635270","id":"PMC_36635270","title":"CircRNA MBOAT2 promotes intrahepatic cholangiocarcinoma progression and lipid metabolism reprogramming by stabilizing PTBP1 to facilitate FASN mRNA cytoplasmic export.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36635270","citation_count":59,"is_preprint":false},{"pmid":"36552896","id":"PMC_36552896","title":"Lactobacillus salivarius SNK-6 Regulates Liver Lipid Metabolism Partly via the miR-130a-5p/MBOAT2 Pathway in a NAFLD Model of Laying Hens.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36552896","citation_count":26,"is_preprint":false},{"pmid":"32412780","id":"PMC_32412780","title":"Cardiac endurance training alters plasma profiles of circular RNA MBOAT2.","date":"2020","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32412780","citation_count":19,"is_preprint":false},{"pmid":"35571489","id":"PMC_35571489","title":"Identification of MBOAT2 as an Unfavorable Biomarker Correlated with KRAS Activation and Reduced CD8+ T-Cell Infiltration in Pancreatic Cancer.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35571489","citation_count":13,"is_preprint":false},{"pmid":"39179098","id":"PMC_39179098","title":"TMAO induces pyroptosis of vascular endothelial cells and atherosclerosis in ApoE-/- mice via MBOAT2-mediated endoplasmic reticulum stress.","date":"2024","source":"Biochimica et biophysica acta. Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/39179098","citation_count":10,"is_preprint":false},{"pmid":"38255868","id":"PMC_38255868","title":"Circ-MBOAT2 Regulates Angiogenesis via the miR-495/NOTCH1 Axis and Associates with Myocardial Perfusion in Patients with Coronary Chronic Total Occlusion.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38255868","citation_count":5,"is_preprint":false},{"pmid":"38315116","id":"PMC_38315116","title":"NAD+ affects differentially expressed genes-MBOAT2-SLC25A21-SOX6 in experimental autoimmune encephalomyelitis model.","date":"2024","source":"The International journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38315116","citation_count":5,"is_preprint":false},{"pmid":"39594462","id":"PMC_39594462","title":"Hyperbaric Oxygen Improves Cognitive Impairment Induced by Hypoxia via Upregulating the Expression of Oleic Acid and MBOAT2 of Mice.","date":"2024","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39594462","citation_count":3,"is_preprint":false},{"pmid":"40088361","id":"PMC_40088361","title":"Pan-cancer analysis predicts MBOAT2 as a potential new ferroptosis related gene immune checkpoint.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40088361","citation_count":2,"is_preprint":false},{"pmid":"41093166","id":"PMC_41093166","title":"FERMT1 suppresses the ferroptosis of glioma cells by interacting with MBOAT2.","date":"2025","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/41093166","citation_count":1,"is_preprint":false},{"pmid":"40201699","id":"PMC_40201699","title":"An active ingredient from the combination of Corydalis Rhizoma and Paeoniae Radix Alba relieves chronic compression injury-induced pain in rats by ameliorating AR/Mboat2-mediated ferroptosis in spinal cord neurons.","date":"2025","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40201699","citation_count":0,"is_preprint":false},{"pmid":"40369698","id":"PMC_40369698","title":"Mechanistic insights into Circ-MBOAT2-mediated regulation of TLK1 through miR-664b-3p in non-small cell lung cancer.","date":"2025","source":"Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/40369698","citation_count":0,"is_preprint":false},{"pmid":"41301966","id":"PMC_41301966","title":"Oleic Acid Improves Goat Sperm Quality by Enhancing the MBOAT2/ACSL3 Pathway to Attenuate Ferroptosis.","date":"2025","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/41301966","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.02.686003","title":"MBOAT2 limits the amounts of PUFA in phosphatidylcholine of neonatal and dystrophic skeletal muscle and promotes muscle regeneration","date":"2025-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.02.686003","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10236,"output_tokens":1611,"usd":0.027436,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8469,"output_tokens":2231,"usd":0.04906,"stage2_stop_reason":"end_turn"},"total_usd":0.076496,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"MBOAT2 overexpression disrupts glycerophospholipid metabolism and induces endothelial cell pyroptosis in an endoplasmic reticulum stress-dependent manner; genetic upregulation of MBOAT2 via AAV with endothelium-specific promoter increases atherosclerotic lesions in ApoE-/- mice, and TMAO promotes this pathway by upregulating MBOAT2 expression.\",\n      \"method\": \"AAV-mediated endothelium-specific MBOAT2 overexpression in ApoE-/- mice, lipidomic analysis of glycerophospholipid metabolism, ER stress assays, pyroptosis readouts\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function with defined phenotypic readout (atherosclerosis, pyroptosis) and mechanistic pathway (ER stress), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39179098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FERMT1 physically interacts with MBOAT2 to suppress ferroptosis in glioma cells; depletion of MBOAT2 abolishes the anti-ferroptotic effects of FERMT1, and MBOAT2 overexpression rescues ferroptosis in FERMT1-deficient cells, defining a FERMT1-MBOAT2 axis that regulates ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation (interaction), gain- and loss-of-function experiments, erastin-induced ferroptosis assay, ferrostatin-1 rescue\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined ferroptosis phenotype and rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41093166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MBOAT2 functions as a lysophospholipid acyltransferase that limits the incorporation of polyunsaturated fatty acids (PUFAs) into phosphatidylcholine (PC), thereby enriching monounsaturated fatty acids (MUFAs) in PC; this activity is highly induced in activated satellite cells and promotes muscle regeneration by buffering oxidative stress from lipid peroxidation.\",\n      \"method\": \"Lipidomic profiling, loss- and gain-of-function experiments in skeletal muscle/satellite cells, enzymatic characterization as lysophospholipid acyltransferase\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — enzymatic activity established with lipidomic profiling and loss/gain-of-function, but preprint (single lab, not yet peer-reviewed)\",\n      \"pmids\": [\"bio_10.1101_2025.11.02.686003\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In hypoxia-induced cognitive impairment, HBO therapy upregulates MBOAT2 and oleic acid, leading to membrane phospholipid remodeling; in vitro experiments confirmed that oleic acid and MBOAT2 act in a mutually dependent manner to remodel membrane phospholipids and reduce neuronal ferroptosis.\",\n      \"method\": \"In vivo hypoxia mouse model with HBO treatment, metabolomic/lipidomic analysis, in vitro cell experiments with MBOAT2 and oleic acid manipulation, molecular biology\",\n      \"journal\": \"Antioxidants (Basel, Switzerland)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic detail in abstract, mutual dependence of OA and MBOAT2 stated but not fully dissected\",\n      \"pmids\": [\"39594462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AR (androgen receptor) acts as an upstream signaling molecule of MBOAT2; YB60 treatment increases AR and MBOAT2 expression in spinal cord neurons, and knockdown of AR eliminates YB60-induced upregulation of MBOAT2 and its anti-ferroptotic effects, placing MBOAT2 downstream of AR in a ferroptosis-regulatory pathway.\",\n      \"method\": \"Western blotting, immunofluorescent dual staining, AR knockdown in PC12 cells, erastin-induced ferroptosis model\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single genetic manipulation (AR knockdown) with MBOAT2 readout, limited mechanistic depth\",\n      \"pmids\": [\"40201699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MBOAT2 overexpression in pancreatic cancer cells accelerates cell proliferation and migration and enhances CDK2 and CCNA2 expression, promoting cell cycle progression from G1 to G2 phase.\",\n      \"method\": \"MTT, colony formation, Transwell assays, flow cytometry cell cycle analysis, western blot\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression with phenotypic readouts but limited mechanistic pathway dissection\",\n      \"pmids\": [\"35571489\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MBOAT2 is a lysophospholipid acyltransferase that remodels membrane phosphatidylcholine by incorporating monounsaturated fatty acids at the expense of polyunsaturated fatty acids, thereby suppressing lipid peroxidation and ferroptosis; it operates downstream of androgen receptor signaling and physically interacts with FERMT1 to regulate ferroptosis in cancer cells, while its dysregulation in endothelial cells disrupts glycerophospholipid metabolism, induces ER stress-dependent pyroptosis, and promotes atherosclerosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MBOAT2 is a lysophospholipid acyltransferase that remodels membrane phospholipid composition by limiting the incorporation of polyunsaturated fatty acids into phosphatidylcholine while enriching monounsaturated fatty acids, an activity that buffers oxidative stress from lipid peroxidation and thereby suppresses ferroptosis [#2]. Through this membrane-remodeling function it acts as a protective factor in multiple settings: its induction in activated satellite cells promotes muscle regeneration [#2], and in neurons it cooperates with oleic acid in a mutually dependent manner to reduce ferroptosis [#3]. The anti-ferroptotic activity of MBOAT2 is governed by upstream regulators and physical partners — androgen receptor signaling drives MBOAT2 expression to limit neuronal ferroptosis [#4], and FERMT1 physically interacts with MBOAT2 to suppress ferroptosis, an effect that requires MBOAT2 and is restored by its overexpression in FERMT1-deficient cells [#1]. In endothelial cells, gain of MBOAT2 disrupts glycerophospholipid metabolism and triggers endoplasmic reticulum stress-dependent pyroptosis, and endothelium-specific overexpression aggravates atherosclerosis in ApoE-/- mice, a pathway induced by TMAO [#0]. MBOAT2 overexpression also accelerates proliferation, migration, and cell cycle progression in pancreatic cancer cells [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2022,\n      \"claim\": \"An initial link between MBOAT2 and cancer cell behavior was established, showing that elevated MBOAT2 can drive proliferation and cell cycle progression.\",\n      \"evidence\": \"MBOAT2 overexpression with proliferation, migration, and flow cytometry cell-cycle assays in pancreatic cancer cells\",\n      \"pmids\": [\"35571489\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single overexpression study without mechanistic dissection of how MBOAT2 enzymatic activity drives CDK2/CCNA2 induction\", \"No link to lipid remodeling or ferroptosis in this context\", \"Loss-of-function not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"MBOAT2 was implicated as a pathogenic effector in vascular disease, defining a context where its overexpression is harmful rather than protective.\",\n      \"evidence\": \"AAV endothelium-specific MBOAT2 overexpression in ApoE-/- mice with lipidomics, ER stress, and pyroptosis readouts\",\n      \"pmids\": [\"39179098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between glycerophospholipid disruption and ER stress not fully mapped\", \"Direct enzymatic mechanism in endothelial cells not characterized\", \"How TMAO upregulates MBOAT2 transcriptionally is unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"MBOAT2 was tied to neuronal protection through membrane phospholipid remodeling and a dependency on oleic acid.\",\n      \"evidence\": \"Hypoxia mouse model with HBO therapy, lipidomic analysis, and in vitro MBOAT2/oleic acid manipulation\",\n      \"pmids\": [\"39594462\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mutual dependence of oleic acid and MBOAT2 stated but not mechanistically dissected\", \"Direct enzymatic assay not performed in this system\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The enzymatic identity of MBOAT2 as a lysophospholipid acyltransferase favoring MUFA over PUFA incorporation into PC was established, providing the biochemical basis for its anti-ferroptotic role.\",\n      \"evidence\": \"Lipidomic profiling and loss/gain-of-function in satellite cells with enzymatic characterization (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.02.686003\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Substrate specificity and structural basis of acyl-chain selectivity not defined\", \"Generalizability beyond muscle regeneration to be confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Upstream and physical regulators of MBOAT2 in ferroptosis were identified, placing it downstream of androgen receptor and in complex with FERMT1.\",\n      \"evidence\": \"AR knockdown in PC12 cells and Co-IP plus reciprocal gain/loss-of-function with erastin/ferrostatin-1 ferroptosis assays in glioma cells\",\n      \"pmids\": [\"40201699\", \"41093166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AR regulates MBOAT2 directly at the transcriptional level is unknown\", \"FERMT1-MBOAT2 interaction interface and stoichiometry not defined\", \"Single Co-IP without reciprocal/structural validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MBOAT2's single acyltransferase activity produces opposite outcomes — protective anti-ferroptotic remodeling versus pathogenic glycerophospholipid disruption and pyroptosis — across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model reconciling protective versus pathogenic phenotypes\", \"No structural data on substrate selectivity\", \"Direct enzymatic kinetics not reported in peer-reviewed work\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FERMT1\", \"AR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}