{"gene":"MBOAT2","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2024,"finding":"MBOAT2, a phospholipid-modifying enzyme, disrupts glycerophospholipid metabolism and induces endothelial cell pyroptosis in an endoplasmic reticulum stress-dependent manner. Genetic upregulation of MBOAT2 via adeno-associated virus with endothelium-specific promoter increased atherosclerotic lesions in ApoE-/- mice, and TMAO promotes this pathway by upregulating MBOAT2 expression.","method":"AAV-mediated endothelium-specific overexpression in ApoE-/- mice, glycerophospholipid metabolic profiling, endoplasmic reticulum stress assays","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo gain-of-function with defined mechanistic pathway (ER stress-dependent pyroptosis), single lab","pmids":["39179098"],"is_preprint":false},{"year":2025,"finding":"FERMT1 interacts with MBOAT2 to suppress ferroptosis in glioma cells. Depletion of MBOAT2 abolishes the anti-ferroptotic effects of FERMT1, whereas MBOAT2 overexpression rescues ferroptosis in FERMT1-deficient cells, establishing a FERMT1-MBOAT2 axis in ferroptosis regulation.","method":"Co-immunoprecipitation/interaction assays, gain- and loss-of-function experiments, erastin-induced ferroptosis assay, ferrostatin-1 rescue","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal functional epistasis with ferroptosis inhibitor rescue, single lab","pmids":["41093166"],"is_preprint":false},{"year":2025,"finding":"MBOAT2 functions as a lysophospholipid acyltransferase that limits polyunsaturated fatty acid (PUFA) incorporation into phosphatidylcholine (PC), enriching monounsaturated fatty acids (MUFAs) in PC. This remodeling activity promotes myogenic repair in skeletal muscle and buffers oxidative stress; loss- and gain-of-function approaches confirmed MBOAT2 remodels PC composition in muscle.","method":"Lipidomic profiling, loss- and gain-of-function genetic approaches in satellite cells and dystrophic/neonatal muscle","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 — enzymatic activity confirmed by lipidomics with loss/gain-of-function, single lab, preprint","pmids":["bio_10.1101_2025.11.02.686003"],"is_preprint":true},{"year":2024,"finding":"MBOAT2 and oleic acid (OA) mediate membrane phospholipid remodeling in a mutually dependent manner. Upregulation of MBOAT2 by hyperbaric oxygen alters membrane phospholipid composition (increasing oleic acid incorporation) and reduces hypoxia-induced neuronal ferroptosis, confirmed by in vitro experiments.","method":"Lipidomic and metabolomic analyses, molecular biology, in vitro cell experiments with OA and MBOAT2 manipulation","journal":"Antioxidants (Basel, Switzerland)","confidence":"Low","confidence_rationale":"Tier 3 — single lab, mechanistic inference from lipidomics and OE/KD, limited orthogonal validation","pmids":["39594462"],"is_preprint":false},{"year":2025,"finding":"Androgen receptor (AR) acts as an upstream signaling molecule regulating MBOAT2 expression. YB60 treatment upregulates AR and MBOAT2 in spinal cord neurons to inhibit ferroptosis; knockdown of AR eliminated upregulation of MBOAT2 and the anti-ferroptotic effects, placing AR upstream of MBOAT2 in spinal cord ferroptosis regulation.","method":"Western blotting, immunofluorescent dual staining, AR knockdown in PC12 cells, erastin-induced ferroptosis assay","journal":"Frontiers in pharmacology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, epistasis by KD, single method per interaction","pmids":["40201699"],"is_preprint":false}],"current_model":"MBOAT2 is a lysophospholipid acyltransferase that remodels phosphatidylcholine by limiting PUFA incorporation and enriching MUFAs, thereby reducing lipid peroxidation and ferroptosis; it is regulated upstream by the androgen receptor (AR), interacts with FERMT1 to suppress ferroptosis, and when overexpressed disrupts glycerophospholipid metabolism to induce ER stress-dependent pyroptosis in endothelial cells."},"narrative":{"teleology":[{"year":2024,"claim":"Establishing that MBOAT2 overexpression disrupts glycerophospholipid homeostasis in endothelial cells revealed a pro-atherogenic mechanism: ER stress-dependent pyroptosis driven by MBOAT2-mediated lipid remodeling.","evidence":"AAV-mediated endothelium-specific MBOAT2 overexpression in ApoE−/− mice with metabolic profiling and ER stress assays","pmids":["39179098"],"confidence":"Medium","gaps":["Endogenous MBOAT2 loss-of-function in endothelial cells was not tested","Specific phospholipid species driving ER stress were not identified","No independent replication by another group"]},{"year":2024,"claim":"Linking MBOAT2 to oleic acid-dependent membrane remodeling and neuronal ferroptosis protection provided the first evidence that MBOAT2 preferentially channels monounsaturated fatty acids into membrane phospholipids to buffer lipid peroxidation.","evidence":"Lipidomic and metabolomic analyses with MBOAT2 manipulation under hyperbaric oxygen and hypoxia in neuronal cells","pmids":["39594462"],"confidence":"Low","gaps":["Awaits orthogonal enzymatic reconstitution or in vitro acyltransferase assay","MUFA vs. PUFA selectivity inferred from lipid profiles, not from direct substrate specificity measurement","Single lab, single cell model"]},{"year":2025,"claim":"Demonstrating that FERMT1 physically interacts with MBOAT2 and that MBOAT2 is epistatic to FERMT1 in ferroptosis suppression established a protein-level regulatory axis controlling ferroptosis through phospholipid remodeling.","evidence":"Co-immunoprecipitation and reciprocal gain/loss-of-function with erastin-induced ferroptosis and ferrostatin-1 rescue in glioma cells","pmids":["41093166"],"confidence":"Medium","gaps":["Structural basis and binding domain for the FERMT1–MBOAT2 interaction are unknown","Whether FERMT1 modulates MBOAT2 enzymatic activity or merely its stability/localization is unresolved","Findings limited to glioma cell lines"]},{"year":2025,"claim":"Placing AR upstream of MBOAT2 transcriptional regulation showed that hormonal signaling can control membrane lipid remodeling and ferroptosis via MBOAT2, broadening the upstream regulatory landscape.","evidence":"AR knockdown abolishes MBOAT2 upregulation and anti-ferroptotic effects in PC12 cells; Western blot and immunofluorescence","pmids":["40201699"],"confidence":"Low","gaps":["Direct AR binding to the MBOAT2 promoter was not demonstrated (e.g., ChIP)","Single cell line, single knockdown method","Whether AR regulation of MBOAT2 is generalizable beyond spinal cord neurons is unknown"]},{"year":2025,"claim":"Confirming MBOAT2 as a bona fide lysophospholipid acyltransferase that limits PUFA-containing PC and enriches MUFA-PC provided direct enzymatic characterization, unifying the anti-ferroptotic and pro-repair functions under a single biochemical activity.","evidence":"Lipidomic profiling with loss- and gain-of-function in satellite cells and dystrophic/neonatal muscle (preprint)","pmids":["bio_10.1101_2025.11.02.686003"],"confidence":"Medium","gaps":["Preprint; not yet peer-reviewed","In vitro reconstitution of acyltransferase activity with purified protein has not been reported","Substrate selectivity determinants at the structural level remain uncharacterized"]},{"year":null,"claim":"The in vitro enzymatic kinetics of MBOAT2, its structural basis for MUFA selectivity, and the full repertoire of its upstream regulators and tissue-specific roles remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of MBOAT2","No purified enzyme kinetics for acyltransferase activity","Unresolved whether MBOAT2's pro-pyroptotic vs. anti-ferroptotic effects represent dose-dependent or context-dependent outcomes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2,3]}],"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":[0,2,3]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,3]}],"complexes":[],"partners":["FERMT1","AR"],"other_free_text":[]},"mechanistic_narrative":"MBOAT2 is a lysophospholipid acyltransferase that remodels phosphatidylcholine by limiting polyunsaturated fatty acid (PUFA) incorporation and enriching monounsaturated fatty acids (MUFAs), thereby reducing membrane susceptibility to lipid peroxidation and ferroptosis [PMID:41093166, bio_10.1101_2025.11.02.686003]. This phospholipid remodeling activity protects diverse cell types—including neurons, glioma cells, and satellite cells—from oxidative stress-induced ferroptosis, and MBOAT2 functionally cooperates with FERMT1, which interacts with MBOAT2 to suppress ferroptosis in an MBOAT2-dependent manner [PMID:41093166]. Overexpression of MBOAT2 in endothelial cells disrupts glycerophospholipid metabolism sufficiently to induce endoplasmic reticulum stress-dependent pyroptosis and promotes atherosclerotic lesion formation in vivo [PMID:39179098]."},"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":60,"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":57,"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":8,"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":9460,"output_tokens":1351,"usd":0.024323},"stage2":{"model":"claude-opus-4-6","input_tokens":4568,"output_tokens":1781,"usd":0.101047},"total_usd":0.12537,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"MBOAT2, a phospholipid-modifying enzyme, disrupts glycerophospholipid metabolism and induces endothelial cell pyroptosis in an endoplasmic reticulum stress-dependent manner. Genetic upregulation of MBOAT2 via adeno-associated virus with endothelium-specific promoter increased atherosclerotic lesions in ApoE-/- mice, and TMAO promotes this pathway by upregulating MBOAT2 expression.\",\n      \"method\": \"AAV-mediated endothelium-specific overexpression in ApoE-/- mice, glycerophospholipid metabolic profiling, endoplasmic reticulum stress assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain-of-function with defined mechanistic pathway (ER stress-dependent pyroptosis), single lab\",\n      \"pmids\": [\"39179098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FERMT1 interacts with MBOAT2 to suppress ferroptosis in glioma cells. Depletion of MBOAT2 abolishes the anti-ferroptotic effects of FERMT1, whereas MBOAT2 overexpression rescues ferroptosis in FERMT1-deficient cells, establishing a FERMT1-MBOAT2 axis in ferroptosis regulation.\",\n      \"method\": \"Co-immunoprecipitation/interaction assays, 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 2-3 — reciprocal functional epistasis with ferroptosis inhibitor rescue, single lab\",\n      \"pmids\": [\"41093166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MBOAT2 functions as a lysophospholipid acyltransferase that limits polyunsaturated fatty acid (PUFA) incorporation into phosphatidylcholine (PC), enriching monounsaturated fatty acids (MUFAs) in PC. This remodeling activity promotes myogenic repair in skeletal muscle and buffers oxidative stress; loss- and gain-of-function approaches confirmed MBOAT2 remodels PC composition in muscle.\",\n      \"method\": \"Lipidomic profiling, loss- and gain-of-function genetic approaches in satellite cells and dystrophic/neonatal muscle\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — enzymatic activity confirmed by lipidomics with loss/gain-of-function, single lab, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.11.02.686003\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MBOAT2 and oleic acid (OA) mediate membrane phospholipid remodeling in a mutually dependent manner. Upregulation of MBOAT2 by hyperbaric oxygen alters membrane phospholipid composition (increasing oleic acid incorporation) and reduces hypoxia-induced neuronal ferroptosis, confirmed by in vitro experiments.\",\n      \"method\": \"Lipidomic and metabolomic analyses, molecular biology, in vitro cell experiments with OA and MBOAT2 manipulation\",\n      \"journal\": \"Antioxidants (Basel, Switzerland)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mechanistic inference from lipidomics and OE/KD, limited orthogonal validation\",\n      \"pmids\": [\"39594462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Androgen receptor (AR) acts as an upstream signaling molecule regulating MBOAT2 expression. YB60 treatment upregulates AR and MBOAT2 in spinal cord neurons to inhibit ferroptosis; knockdown of AR eliminated upregulation of MBOAT2 and the anti-ferroptotic effects, placing AR upstream of MBOAT2 in spinal cord ferroptosis regulation.\",\n      \"method\": \"Western blotting, immunofluorescent dual staining, AR knockdown in PC12 cells, erastin-induced ferroptosis assay\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, epistasis by KD, single method per interaction\",\n      \"pmids\": [\"40201699\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MBOAT2 is a lysophospholipid acyltransferase that remodels phosphatidylcholine by limiting PUFA incorporation and enriching MUFAs, thereby reducing lipid peroxidation and ferroptosis; it is regulated upstream by the androgen receptor (AR), interacts with FERMT1 to suppress ferroptosis, and when overexpressed disrupts glycerophospholipid metabolism to induce ER stress-dependent pyroptosis in endothelial cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MBOAT2 is a lysophospholipid acyltransferase that remodels phosphatidylcholine by limiting polyunsaturated fatty acid (PUFA) incorporation and enriching monounsaturated fatty acids (MUFAs), thereby reducing membrane susceptibility to lipid peroxidation and ferroptosis [PMID:41093166, bio_10.1101_2025.11.02.686003]. This phospholipid remodeling activity protects diverse cell types—including neurons, glioma cells, and satellite cells—from oxidative stress-induced ferroptosis, and MBOAT2 functionally cooperates with FERMT1, which interacts with MBOAT2 to suppress ferroptosis in an MBOAT2-dependent manner [PMID:41093166]. Overexpression of MBOAT2 in endothelial cells disrupts glycerophospholipid metabolism sufficiently to induce endoplasmic reticulum stress-dependent pyroptosis and promotes atherosclerotic lesion formation in vivo [PMID:39179098].\",\n  \"teleology\": [\n    {\n      \"year\": 2024,\n      \"claim\": \"Establishing that MBOAT2 overexpression disrupts glycerophospholipid homeostasis in endothelial cells revealed a pro-atherogenic mechanism: ER stress-dependent pyroptosis driven by MBOAT2-mediated lipid remodeling.\",\n      \"evidence\": \"AAV-mediated endothelium-specific MBOAT2 overexpression in ApoE−/− mice with metabolic profiling and ER stress assays\",\n      \"pmids\": [\"39179098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endogenous MBOAT2 loss-of-function in endothelial cells was not tested\",\n        \"Specific phospholipid species driving ER stress were not identified\",\n        \"No independent replication by another group\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linking MBOAT2 to oleic acid-dependent membrane remodeling and neuronal ferroptosis protection provided the first evidence that MBOAT2 preferentially channels monounsaturated fatty acids into membrane phospholipids to buffer lipid peroxidation.\",\n      \"evidence\": \"Lipidomic and metabolomic analyses with MBOAT2 manipulation under hyperbaric oxygen and hypoxia in neuronal cells\",\n      \"pmids\": [\"39594462\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Awaits orthogonal enzymatic reconstitution or in vitro acyltransferase assay\",\n        \"MUFA vs. PUFA selectivity inferred from lipid profiles, not from direct substrate specificity measurement\",\n        \"Single lab, single cell model\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that FERMT1 physically interacts with MBOAT2 and that MBOAT2 is epistatic to FERMT1 in ferroptosis suppression established a protein-level regulatory axis controlling ferroptosis through phospholipid remodeling.\",\n      \"evidence\": \"Co-immunoprecipitation and reciprocal gain/loss-of-function with erastin-induced ferroptosis and ferrostatin-1 rescue in glioma cells\",\n      \"pmids\": [\"41093166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis and binding domain for the FERMT1–MBOAT2 interaction are unknown\",\n        \"Whether FERMT1 modulates MBOAT2 enzymatic activity or merely its stability/localization is unresolved\",\n        \"Findings limited to glioma cell lines\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placing AR upstream of MBOAT2 transcriptional regulation showed that hormonal signaling can control membrane lipid remodeling and ferroptosis via MBOAT2, broadening the upstream regulatory landscape.\",\n      \"evidence\": \"AR knockdown abolishes MBOAT2 upregulation and anti-ferroptotic effects in PC12 cells; Western blot and immunofluorescence\",\n      \"pmids\": [\"40201699\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Direct AR binding to the MBOAT2 promoter was not demonstrated (e.g., ChIP)\",\n        \"Single cell line, single knockdown method\",\n        \"Whether AR regulation of MBOAT2 is generalizable beyond spinal cord neurons is unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Confirming MBOAT2 as a bona fide lysophospholipid acyltransferase that limits PUFA-containing PC and enriches MUFA-PC provided direct enzymatic characterization, unifying the anti-ferroptotic and pro-repair functions under a single biochemical activity.\",\n      \"evidence\": \"Lipidomic profiling with loss- and gain-of-function in satellite cells and dystrophic/neonatal muscle (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.02.686003\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint; not yet peer-reviewed\",\n        \"In vitro reconstitution of acyltransferase activity with purified protein has not been reported\",\n        \"Substrate selectivity determinants at the structural level remain uncharacterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The in vitro enzymatic kinetics of MBOAT2, its structural basis for MUFA selectivity, and the full repertoire of its upstream regulators and tissue-specific roles remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of MBOAT2\",\n        \"No purified enzyme kinetics for acyltransferase activity\",\n        \"Unresolved whether MBOAT2's pro-pyroptotic vs. anti-ferroptotic effects represent dose-dependent or context-dependent outcomes\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0016740\",\n        \"supporting_discovery_ids\": [0, 2, 3]\n      },\n      {\n        \"term_id\": \"GO:0008289\",\n        \"supporting_discovery_ids\": [2, 3]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005783\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1430728\",\n        \"supporting_discovery_ids\": [0, 2, 3]\n      },\n      {\n        \"term_id\": \"R-HSA-5357801\",\n        \"supporting_discovery_ids\": [0, 1, 3]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FERMT1\",\n      \"AR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}