{"gene":"MBOAT7","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2023,"finding":"Cryo-EM structure of human MBOAT7 revealed that arachidonyl-CoA and lyso-PI access the catalytic center through a twisted tunnel from the cytosol and lumenal sides, respectively. N-terminal residues on the ER lumenal side determine phospholipid headgroup selectivity: swapping N-terminal residues between MBOATs 1, 5, and 7 converts enzyme specificity for different lyso-phospholipids. The structure also enabled virtual screening-based identification of small-molecule inhibitors.","method":"Cryo-EM structure determination, domain-swap mutagenesis, virtual screening, in vitro acyltransferase assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic structure combined with functional mutagenesis (domain swaps converting substrate specificity) and in vitro activity assays in a single rigorous study","pmids":["37316513"],"is_preprint":false},{"year":2021,"finding":"Purified recombinant human MBOAT7 preferentially transfers polyunsaturated fatty acids (20:4 arachidonic acid and 20:5 EPA) to lysophosphatidylinositol (LPI). Missense mutations at the putative catalytic dyad residues N321A and H356A, individually or combined, abolish O-acyltransferase activity, establishing these residues as essential catalytic residues.","method":"In vitro acyltransferase assay with radiolabeled fatty acids using purified recombinant wild-type and mutant MBOAT7 expressed in Pichia pastoris","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution with purified protein plus active-site mutagenesis, single lab but multiple orthogonal approaches","pmids":["33513444"],"is_preprint":false},{"year":2019,"finding":"MBOAT7 is an integral multispanning transmembrane protein anchored to endomembranes with six transmembrane domains. The predicted catalytic dyad (Asn-321 and His-356) has a lumenal localization. This topology was established using solubilization of membrane fractions, GFP/FLAG-tagged truncation constructs, selective membrane permeabilization, co-immunofluorescence, and Fluorescence Protease Protection (FPP) assay in living cells.","method":"Fluorescence Protease Protection (FPP) assay, selective membrane permeabilization with indirect immunofluorescence, Western blotting, in silico topology prediction (22 methods)","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal experimental approaches (FPP, selective permeabilization, immunofluorescence) converging on the same six-TM topology model","pmids":["30959108"],"is_preprint":false},{"year":2012,"finding":"LPIAT1/MBOAT7 is the enzyme responsible for incorporating arachidonic acid (AA) into phosphatidylinositol (PI) in mammals. Lpiat1-knockout mice show near-complete loss of LPIAT activity with arachidonoyl-CoA, reduced AA in PI and PI-phosphates, cortical atrophy, hippocampal atrophy, disordered cortical lamination, delayed neuronal migration, and reduced neurite outgrowth in vitro.","method":"Gene knockout (Lpiat1−/− mice), in vitro LPIAT activity assay, lipidomics, immunohistochemistry, neurite outgrowth assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — combined enzymatic activity measurement, lipidomics, and in vivo/in vitro phenotypic analysis in knockout mice","pmids":["23097495"],"is_preprint":false},{"year":2013,"finding":"LPIAT1/MBOAT7 plays a non-redundant role in maintaining physiological levels of PtdIns and PtdInsP2 through an active deacylation/reacylation (Lands) cycle. Knockout mice show a 26–44% reduction in total PtdIns and PtdInsP2 in brain and liver, a 300–525% increase in C18:0 lyso-PtdIns, and a selective reduction of C38:4 (arachidonoyl-containing) species, with no compensation from other molecular species.","method":"Gene knockout mouse (LPIAT1−/−), LC-ESI/MS lipidomics of liver and brain","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive LC-MS lipidomics in knockout tissue, replicated across two tissue types, independent of the 2012 study","pmids":["23472195"],"is_preprint":false},{"year":2019,"finding":"Mboat7 loss of function in mice (but not Tmc4 loss) is sufficient to promote NAFLD progression under high-fat diet. Mboat7 knockdown leads to accumulation of lysophosphatidylinositol (LPI) substrates. Direct hepatic administration of LPI promotes inflammatory and fibrotic transcriptional changes in an Mboat7-dependent manner, establishing LPI accumulation as the mechanistic driver of liver disease.","method":"Antisense oligonucleotide (ASO) knockdown in mice, hepatic LPI administration, transcriptional profiling, lipidomics","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss-of-function with genetic specificity (Mboat7 vs Tmc4), direct LPI administration rescue/phenocopy experiment, multiple readouts","pmids":["31621579"],"is_preprint":false},{"year":2020,"finding":"Hepatocyte-specific Lpiat1/MBOAT7 knockout mice develop spontaneous hepatic steatosis and fibrosis on high-fat diet. The mechanism involves increased PI turnover: reduced PI acyl-chain remodeling stimulates both PI synthesis and breakdown; PI degradation by phospholipase C produces diacylglycerol (DAG), a precursor to triglyceride synthesis, fueling steatosis through this non-canonical pathway.","method":"Hepatocyte-specific Lpiat1 knockout mouse, CRISPR-Cas9 and siRNA depletion in human hepatic cells, radiolabeled glycerol/fatty acid metabolic flux, LC-ESI-MS lipidomics, liver spheroid model","journal":"Gut","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple model systems (mouse KO, human cell CRISPR, spheroids), metabolic flux tracing, and lipidomics establishing pathway mechanism","pmids":["32253259"],"is_preprint":false},{"year":2020,"finding":"Hepatocyte-specific deletion of Mboat7 causes spontaneous steatosis characterized by increased hepatic cholesterol ester content and, on a fibrogenic diet, increased fibrosis independent of inflammation. Lipidomics of knockout mice and human rs641738TT carriers both show increased total lysophosphatidylinositol levels and similar alterations in LPI/PI subspecies, indicating inflammation-independent lipid-signaling-mediated fibrogenesis.","method":"Hepatocyte-specific Mboat7 knockout mouse (Mboat7Δhep), picrosirius staining, hydroxyproline quantification, RNA sequencing, flow cytometry, LC-MS lipidomics of mouse liver and human liver biopsies","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent model systems (mouse KO and human genotyped liver biopsies) with converging lipidomic evidence, multiple orthogonal methods","pmids":["32591434"],"is_preprint":false},{"year":2021,"finding":"Hepatic deletion of Mboat7 (Mboat7 LSKO mice) causes fatty liver associated with activation of SREBP-1c and increased de novo lipogenesis. Lipidomics showed selective reduction of 20-carbon PUFA-containing phosphatidylinositols. Co-deletion of SREBP cleavage-activating protein (Scap) with Mboat7 normalized hepatic triglycerides, establishing that increased SREBP-1c processing is required for Mboat7 loss-induced steatosis.","method":"Liver-specific Mboat7 knockout mice, compound Mboat7/Scap double-KO, LC-MS lipidomics, gene expression analysis","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by double-KO rescue experiment, supported by lipidomics and gene expression, single lab with multiple orthogonal methods","pmids":["32859645"],"is_preprint":false},{"year":2020,"finding":"Hyperinsulinemia down-regulates hepatic MBOAT7 expression, contributing to steatosis. MBOAT7 deletion in hepatocytes reduces arachidonic acid incorporation into phosphatidylinositol, causes accumulation of saturated triglycerides, enhances lipogenesis, and upregulates fatty acid transporter FATP1. FATP1 deletion rescues the steatosis phenotype, placing FATP1 downstream of MBOAT7 loss.","method":"CRISPR/Cas9 knockout in HepG2 cells, antisense oligonucleotide silencing in C57Bl/6 mice, siRNA, lipid mass spectrometry, FATP1 rescue experiment","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by FATP1 deletion rescue, multiple model systems (in vivo ASO + in vitro CRISPR), lipidomic confirmation","pmids":["32058943"],"is_preprint":false},{"year":2023,"finding":"MMD (a Golgi-resident scaffold protein) physically interacts with both ACSL4 and MBOAT7, two enzymes that catalyze sequential steps to incorporate arachidonic acid (AA) into phosphatidylinositol (PI). MMD promotes ferroptosis susceptibility in ovarian and renal carcinoma cells in an ACSL4- and MBOAT7-dependent manner by increasing flux of AA into PI, elevating AA-PI and other AA-containing phospholipid species.","method":"Co-immunoprecipitation (Co-IP) of MMD with ACSL4 and MBOAT7, genome editing (MBOAT7 KO), lipidomics, ferroptosis cell death assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP establishing ternary complex, supported by KO lipidomics and functional ferroptosis readout, single lab","pmids":["37691145"],"is_preprint":false},{"year":2020,"finding":"ACSL3 channels arachidonic acid (AA) into phosphatidylinositols to provide LPIAT1/MBOAT7 with an AA pool to sustain elevated prostaglandin synthesis in non-small cell lung cancer. LPIAT1 knockdown suppresses proliferation, anchorage-independent growth, and in vivo tumorigenesis in KrasG12D-driven lung cancer models, establishing an ACSL3-LPIAT1 signaling axis for prostaglandin production.","method":"siRNA knockdown of LPIAT1 in lung cancer cell lines, KrasG12D mouse models, proliferation and anchorage-independent growth assays, in vivo tumorigenesis assay, lipidomics","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular pathway placement (ACSL3→LPIAT1→AA-PI→prostaglandins), in vitro and in vivo phenotypes, single lab","pmids":["32034305"],"is_preprint":false},{"year":2022,"finding":"MBOAT7 acts as a negative regulator of toll-like receptor (TLR) signaling in macrophages. MBOAT7 deficiency alters membrane phospholipid composition, redistributing arachidonic acid toward proinflammatory eicosanoids, inducing ER stress, mitochondrial dysfunction, and remodeling of the inflammatory-related chromatin landscape, culminating in enhanced macrophage TLR responses. Activation of MBOAT7 reverses these effects.","method":"MBOAT7 knockdown/activation in macrophages, phospholipidomics, eicosanoid profiling, ER stress markers, mitochondrial function assays, ATAC-seq chromatin accessibility profiling","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal mechanistic readouts (lipidomics, eicosanoids, ER stress, chromatin) in macrophage loss/gain-of-function, single lab","pmids":["36473860"],"is_preprint":false},{"year":2024,"finding":"Hepatocyte-specific (but not myeloid-specific) deletion of Mboat7 exacerbates ethanol-induced liver injury. Lipidomic profiling revealed increased endosomal/lysosomal lipids (bis-monoacylglycerophosphate, phosphatidylglycerols) in ethanol-exposed Mboat7-HSKO mice. Mechanistically, Mboat7 loss impairs TFEB-mediated lysosomal biogenesis and causes autophagosome accumulation, identifying lysosomal lipid homeostasis dysregulation as a key driver of alcohol-associated liver disease.","method":"Hepatocyte-specific and myeloid-specific Mboat7 conditional knockout mice, lipidomics, autophagic flux assays, TFEB localization/activity assays, liver injury markers","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type specificity established by parallel hepatocyte vs. myeloid KO, comprehensive lipidomics, autophagic flux mechanistic dissection, single lab with multiple orthogonal methods","pmids":["38648183"],"is_preprint":false},{"year":2023,"finding":"Adipocyte-specific genetic deletion of Mboat7 promotes hyperinsulinemia, systemic insulin resistance, and mild fatty liver. Unlike in the liver, MBOAT7 is the major source of arachidonic acid-containing PI pools in adipose tissue. Adipocyte MBOAT7-driven PI biosynthesis is closely linked to diet-induced hyperinsulinemia and insulin resistance.","method":"Adipocyte-specific Mboat7 knockout mice (adiponectin-Cre), hepatocyte-specific Mboat7 knockout mice (albumin-Cre), metabolic phenotyping, lipidomics of adipose tissue and liver","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-autonomous roles established by parallel tissue-specific KOs, lipidomics across tissues, multiple metabolic phenotype readouts","pmids":["36806709"],"is_preprint":false},{"year":2024,"finding":"MBOAT7 restoration in MASH mice lowers hepatocyte TAZ (WWTR1), and hepatocyte MBOAT7 silencing enhances TAZ upregulation. Changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH), establishing a novel MBOAT7→phospholipid→cholesterol trafficking→TAZ→IHH profibrotic axis.","method":"AAV-mediated MBOAT7 restoration in MASH mice, hepatocyte MBOAT7 silencing, TAZ/IHH expression analysis, cholesterol trafficking assays, human liver biopsy analysis","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in vivo with defined pathway placement (MBOAT7→phospholipid→cholesterol→TAZ→IHH), validated in human tissue, single lab","pmids":["38776184"],"is_preprint":false},{"year":2025,"finding":"Mboat7 deficiency impairs indirect neurogenesis in the developing neocortex by compromising radial glial cell (RGC) integrity, resulting in decreased proliferation, impaired differentiation into intermediate progenitor cells, and increased apoptosis. These defects were preceded by Golgi apparatus rounding and reduced apical E-cadherin expression. The Mboat7-deficient cortex displayed reduced PI(4,5)P2 levels, and pharmacological inhibition of PI(4,5)P2 synthesis recapitulated Golgi rounding, placing PI(4,5)P2 reduction downstream of MBOAT7 loss as the cause of RGC dysfunction.","method":"Mboat7 knockout mice, immunohistochemistry of RGC markers, PI(4,5)P2 measurement, pharmacological PI(4,5)P2 synthesis inhibition, Golgi morphology analysis, E-cadherin localization","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mouse KO with cellular phenotype + pharmacological epistasis establishing PI(4,5)P2 as mechanistic link, single lab","pmids":["41488780"],"is_preprint":false},{"year":2025,"finding":"Mboat7 loss in vivo results in massive accumulation of lysophosphatidylinositol (LPI) and hyperactive mTOR signaling. Inhibiting mTOR signaling with rapamycin rescued neuronal migration defects in Mboat7 knockout mice, establishing that MBOAT7-driven polyunsaturated PI synthesis suppresses mTOR activity to enable proper cortical neuronal migration.","method":"Mboat7 knockout mice, LC-MS/MS lipidomics of mouse brain and human neuron cultures during neurodevelopment, mTOR pathway activity assays, mTOR inhibitor (rapamycin) rescue of migration defects","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological rescue (rapamycin) of genetic KO phenotype establishes mTOR epistasis; supported by comprehensive lipidomics in both mouse and human models","pmids":["39742503"],"is_preprint":false},{"year":2025,"finding":"Under physiological conditions, MBOAT7 interacts with CDS2 in the ER to maintain lipid metabolic homeostasis. Disruption of this interaction (CDS2 knockdown or loss of function) triggers an adaptive response in which MBOAT7 translocates from the ER to ER–lipid droplet (LD) contact sites in a RAB1-dependent manner. At ER-LD contacts, MBOAT7 inhibits DGAT2-mediated LD growth and promotes lipolysis.","method":"Co-immunoprecipitation (CDS2-MBOAT7 interaction), CDS2 knockdown, live-cell imaging of MBOAT7 subcellular relocalization, RAB1 dependence assay, DGAT2 activity and LD size assays, lipolysis measurements","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP plus live imaging and functional LD/lipolysis readouts establish novel mechanism, but preprint, single lab, not yet peer reviewed","pmids":["bio_10.1101_2025.08.26.672501"],"is_preprint":true},{"year":2020,"finding":"Genetic deletion of MBOAT7 in clear cell renal cell carcinoma (ccRCC) cells decreases proliferation, induces cell cycle arrest, and prevents tumor formation in vivo. RNAseq of MBOAT7-knockout cells identified alterations in cell migration and extracellular matrix organization that were validated functionally in migration assays. MBOAT7 expression increases with tumor grade in human ccRCC samples.","method":"CRISPR/Cas9 knockout in ccRCC cell lines, proliferation assays, cell cycle analysis, in vivo xenograft assay, RNAseq, migration assays, shotgun lipidomics of human ccRCC tumors","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome editing with multiple cellular and in vivo phenotypic readouts plus lipidomics, single lab","pmids":["32180553"],"is_preprint":false}],"current_model":"MBOAT7 (LPIAT1) is a multispanning integral ER/endomembrane acyltransferase with six transmembrane domains and a lumenal catalytic dyad (Asn-321/His-356) that preferentially transfers polyunsaturated fatty acids—especially arachidonic acid (20:4)—from arachidonoyl-CoA to lysophosphatidylinositol (LPI) to produce arachidonic acid-enriched phosphatidylinositol (PI); cryo-EM structure reveals a twisted tunnel allowing substrate access from cytosolic and lumenal sides with N-terminal residues conferring headgroup selectivity; loss of MBOAT7 function causes LPI accumulation and reduced PI/PI-phosphate pools, which in the liver drives steatosis via a PI→DAG→TG metabolic flux (phospholipase C-mediated) and SREBP-1c activation, and fibrosis via a cholesterol trafficking→TAZ→IHH profibrotic axis; in the brain, loss reduces PI(4,5)P2 levels, impairs radial glial cell integrity and cortical neuronal migration through hyperactivation of mTOR signaling; in adipose tissue MBOAT7-driven PI synthesis controls systemic insulin sensitivity; in macrophages MBOAT7 negatively regulates TLR signaling by limiting free arachidonic acid availability for proinflammatory eicosanoid synthesis; and a physical complex with CDS2 in the ER maintains homeostasis, while RAB1-dependent redistribution to ER–lipid droplet contacts inhibits DGAT2-mediated lipid droplet growth."},"narrative":{"mechanistic_narrative":"MBOAT7 (LPIAT1) is the membrane O-acyltransferase that selectively incorporates polyunsaturated fatty acids—principally arachidonic acid—into phosphatidylinositol, acting as the reacylation arm of a Lands-cycle remodeling pathway that sets the cellular pools of arachidonoyl-PI and downstream phosphoinositides [PMID:33513444, PMID:23097495, PMID:23472195]. It is a six-transmembrane integral endomembrane protein with a lumenally oriented catalytic dyad (Asn-321/His-356) whose mutation abolishes activity; cryo-EM shows arachidonoyl-CoA and lyso-PI entering the catalytic center through a twisted tunnel from the cytosolic and lumenal sides, with N-terminal lumenal residues dictating phospholipid headgroup selectivity [PMID:37316513, PMID:33513444, PMID:30959108]. Loss of MBOAT7 causes accumulation of lysophosphatidylinositol and depletion of arachidonoyl-PI and PI-phosphate species, and this lipid imbalance is the proximal driver of its disease phenotypes [PMID:23472195, PMID:31621579, PMID:32591434]. In the liver, MBOAT7 deficiency promotes steatosis and fibrosis through several convergent routes: increased PI turnover feeding a phospholipase C-derived DAG→triglyceride flux, SREBP-1c activation (rescued by Scap co-deletion), FATP1 upregulation (rescued by FATP1 deletion), and a cholesterol-trafficking→TAZ→Indian hedgehog profibrotic axis, while hepatocyte-specific loss also impairs TFEB-mediated lysosomal biogenesis to worsen alcohol-associated injury [PMID:32253259, PMID:32859645, PMID:32058943, PMID:38648183, PMID:38776184]. Beyond the liver, MBOAT7-driven PI synthesis governs systemic insulin sensitivity in adipose tissue [PMID:36806709], limits free arachidonic acid available for proinflammatory eicosanoid production to restrain macrophage TLR signaling [PMID:36473860], and in the developing neocortex maintains PI(4,5)P2 levels and suppresses mTOR signaling to support radial glial integrity and cortical neuronal migration [PMID:41488780, PMID:39742503]. MBOAT7 forms an ER complex with CDS2 and, in cancer contexts, channels arachidonic acid into PI to support prostaglandin synthesis, tumor proliferation, and ACSL4/MMD-dependent ferroptosis susceptibility [PMID:37691145, PMID:32034305, PMID:bio_10.1101_2025.08.26.672501].","teleology":[{"year":2012,"claim":"Established the in vivo enzymatic identity of MBOAT7 as the mammalian arachidonate-incorporating enzyme for PI and linked its loss to a neurodevelopmental phenotype.","evidence":"Lpiat1-knockout mice with in vitro LPIAT activity assays, lipidomics, and cortical histology","pmids":["23097495"],"confidence":"High","gaps":["Catalytic residues not yet defined","Structural basis of substrate selectivity unknown"]},{"year":2013,"claim":"Showed that MBOAT7 maintains physiological PI and PIP2 pools through a non-redundant deacylation/reacylation Lands cycle, with no compensation from other species.","evidence":"LC-ESI/MS lipidomics of liver and brain from LPIAT1-knockout mice","pmids":["23472195"],"confidence":"High","gaps":["Tissue-specific consequences of pool depletion not yet dissected","Downstream signaling effects not addressed"]},{"year":2019,"claim":"Defined the six-transmembrane topology and lumenal orientation of the catalytic dyad, framing how substrate access occurs across the membrane.","evidence":"FPP assay, selective permeabilization, immunofluorescence, and in silico topology prediction","pmids":["30959108"],"confidence":"High","gaps":["Atomic structure not yet resolved","Mechanism of substrate channeling unknown"]},{"year":2019,"claim":"Demonstrated that LPI substrate accumulation, not loss of product per se, is the mechanistic driver of MBOAT7-associated liver disease, with genetic specificity over neighboring TMC4.","evidence":"ASO knockdown in mice, direct hepatic LPI administration, transcriptional profiling, lipidomics","pmids":["31621579"],"confidence":"High","gaps":["LPI receptor/effector mediating inflammatory transcription not identified","Link to fibrosis mechanism not yet resolved"]},{"year":2020,"claim":"Dissected multiple convergent hepatic mechanisms by which MBOAT7 loss drives steatosis and fibrosis—PI turnover→DAG→TG flux, FATP1 upregulation, and cholesterol-ester accumulation—across mouse, human cell, and human biopsy systems.","evidence":"Hepatocyte-specific knockout mice, CRISPR/siRNA in human hepatic cells, metabolic flux tracing, lipidomics, FATP1 rescue, genotyped human liver biopsies","pmids":["32253259","32591434","32058943"],"confidence":"High","gaps":["Relative quantitative contribution of each route not weighted","Trigger linking PI imbalance to phospholipase C activation unclear"]},{"year":2020,"claim":"Placed MBOAT7 in oncogenic and ferroptotic lipid-signaling contexts, showing AA-PI flux supports prostaglandin synthesis and tumor growth in lung and renal cancers.","evidence":"siRNA/CRISPR knockout in lung and ccRCC cell lines, KrasG12D and xenograft mouse models, lipidomics, proliferation/migration assays","pmids":["32034305","32180553"],"confidence":"Medium","gaps":["Single-lab studies per cancer type","Causal eicosanoid species not fully defined in ccRCC"]},{"year":2021,"claim":"Provided direct biochemical proof of substrate preference and identified the essential catalytic residues by reconstituting purified enzyme activity.","evidence":"In vitro acyltransferase assay with purified recombinant WT and N321A/H356A mutant MBOAT7 from Pichia pastoris","pmids":["33513444"],"confidence":"High","gaps":["Kinetic regulation by membrane environment not addressed","Acyl-CoA donor specificity range not exhaustively mapped"]},{"year":2021,"claim":"Established SREBP-1c processing as a required node for MBOAT7-loss-induced steatosis via epistasis.","evidence":"Liver-specific Mboat7 knockout and Mboat7/Scap double-knockout mice with lipidomics and expression analysis","pmids":["32859645"],"confidence":"High","gaps":["Signal linking PI depletion to SREBP-1c activation not identified","Interaction with DAG/FATP1 routes not integrated"]},{"year":2022,"claim":"Showed MBOAT7 restrains innate immune signaling by sequestering arachidonic acid away from proinflammatory eicosanoids in macrophages.","evidence":"MBOAT7 knockdown/activation in macrophages, phospholipidomics, eicosanoid profiling, ER stress and mitochondrial assays, ATAC-seq","pmids":["36473860"],"confidence":"Medium","gaps":["Specific TLR adaptor steps affected not defined","Single-lab study"]},{"year":2023,"claim":"Delivered an atomic-resolution model explaining dual-sided substrate access and headgroup selectivity, and enabled inhibitor discovery.","evidence":"Cryo-EM structure, domain-swap mutagenesis between MBOAT1/5/7, virtual screening, in vitro assay","pmids":["37316513"],"confidence":"High","gaps":["Catalytic transition state not captured","Inhibitor efficacy in vivo not established"]},{"year":2023,"claim":"Identified physical and functional partners—MMD scaffolding ACSL4/MBOAT7 for ferroptosis, and a distinct adipose-specific metabolic role controlling systemic insulin sensitivity.","evidence":"Reciprocal Co-IP with lipidomics/ferroptosis assays (MMD), and adipocyte- vs hepatocyte-specific knockout mice with metabolic phenotyping","pmids":["37691145","36806709"],"confidence":"Medium","gaps":["MMD complex stoichiometry/structure unknown","Adipose-to-systemic signaling mediator not defined"]},{"year":2024,"claim":"Extended the hepatic disease mechanism to a cholesterol-trafficking→TAZ→IHH profibrotic axis and to TFEB-dependent lysosomal homeostasis in alcohol-associated injury.","evidence":"AAV MBOAT7 restoration and silencing in MASH mice, hepatocyte vs myeloid conditional knockouts, TAZ/IHH and TFEB/autophagy assays, human biopsies","pmids":["38776184","38648183"],"confidence":"Medium","gaps":["Molecular link from phospholipid change to cholesterol trafficking unresolved","How PI imbalance impairs TFEB activation unknown"]},{"year":2025,"claim":"Resolved the neurodevelopmental mechanism: MBOAT7-driven PI synthesis sustains PI(4,5)P2 and suppresses mTOR to maintain radial glial integrity and enable cortical neuronal migration.","evidence":"Mboat7 knockout mice with PI(4,5)P2 measurement, pharmacological PI(4,5)P2 inhibition, and rapamycin rescue of migration defects; lipidomics in mouse and human neurons","pmids":["41488780","39742503"],"confidence":"High","gaps":["How LPI accumulation activates mTOR mechanistically unknown","Link between PI(4,5)P2 loss and Golgi rounding not molecularly defined"]},{"year":2025,"claim":"Described a CDS2-anchored ER homeostatic interaction and RAB1-dependent redistribution of MBOAT7 to ER–lipid droplet contacts that restrains DGAT2-mediated droplet growth.","evidence":"Co-IP, CDS2 knockdown, live-cell relocalization imaging, RAB1 dependence and DGAT2/lipolysis assays (preprint)","pmids":["bio_10.1101_2025.08.26.672501"],"confidence":"Medium","gaps":["Preprint, single lab, not peer reviewed","Structural basis of CDS2 interaction and the relocalization trigger undefined"]},{"year":null,"claim":"How a single PI-remodeling enzyme integrates its diverse tissue-specific outputs—SREBP-1c, TAZ/IHH, mTOR, TLR, insulin signaling—into a unified lipid-signaling logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model connecting LPI/PI pool changes to the distinct downstream effectors across tissues","Direct LPI sensor/effector not identified","In vivo therapeutic targeting of the enzyme untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,18]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,4,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12]}],"complexes":[],"partners":["CDS2","MMD","ACSL4","ACSL3","DGAT2","RAB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96N66","full_name":"Membrane-bound acylglycerophosphatidylinositol O-acyltransferase MBOAT7","aliases":["1-acylglycerophosphatidylinositol O-acyltransferase","Bladder and breast carcinoma-overexpressed gene 1 protein","Leukocyte receptor cluster member 4","Lysophosphatidylinositol acyltransferase","LPIAT","Lyso-PI acyltransferase","Lysophospholipid acyltransferase 7","LPLAT 7","Membrane-bound O-acyltransferase domain-containing protein 7","O-acyltransferase domain-containing protein 7","h-mboa-7"],"length_aa":472,"mass_kda":52.8,"function":"Acyltransferase which catalyzes the transfer of an acyl group from an acyl-CoA to a lysophosphatidylinositol (1-acylglycerophosphatidylinositol or LPI) leading to the production of a phosphatidylinositol (1,2-diacyl-sn-glycero-3-phosphoinositol or PI) and participates in the reacylation step of the phospholipid remodeling pathway also known as the Lands cycle (PubMed:18094042, PubMed:18772128). Prefers arachidonoyl-CoA as the acyl donor, thus contributing to the regulation of free levels arachidonic acid in cell (PubMed:18094042, PubMed:18772128). In liver, participates in the regulation of triglyceride metabolism through the phosphatidylinositol acyl-chain remodeling regulation (PubMed:32253259)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q96N66/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MBOAT7","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000125505","cell_line_id":"CID000338","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"LBR","stoichiometry":4.0},{"gene":"SGPL1","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000338","total_profiled":1310},"omim":[{"mim_id":"617188","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 57; 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N-terminal residues on the ER lumenal side determine phospholipid headgroup selectivity: swapping N-terminal residues between MBOATs 1, 5, and 7 converts enzyme specificity for different lyso-phospholipids. The structure also enabled virtual screening-based identification of small-molecule inhibitors.\",\n      \"method\": \"Cryo-EM structure determination, domain-swap mutagenesis, virtual screening, in vitro acyltransferase assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic structure combined with functional mutagenesis (domain swaps converting substrate specificity) and in vitro activity assays in a single rigorous study\",\n      \"pmids\": [\"37316513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Purified recombinant human MBOAT7 preferentially transfers polyunsaturated fatty acids (20:4 arachidonic acid and 20:5 EPA) to lysophosphatidylinositol (LPI). Missense mutations at the putative catalytic dyad residues N321A and H356A, individually or combined, abolish O-acyltransferase activity, establishing these residues as essential catalytic residues.\",\n      \"method\": \"In vitro acyltransferase assay with radiolabeled fatty acids using purified recombinant wild-type and mutant MBOAT7 expressed in Pichia pastoris\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution with purified protein plus active-site mutagenesis, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"33513444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MBOAT7 is an integral multispanning transmembrane protein anchored to endomembranes with six transmembrane domains. The predicted catalytic dyad (Asn-321 and His-356) has a lumenal localization. This topology was established using solubilization of membrane fractions, GFP/FLAG-tagged truncation constructs, selective membrane permeabilization, co-immunofluorescence, and Fluorescence Protease Protection (FPP) assay in living cells.\",\n      \"method\": \"Fluorescence Protease Protection (FPP) assay, selective membrane permeabilization with indirect immunofluorescence, Western blotting, in silico topology prediction (22 methods)\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal experimental approaches (FPP, selective permeabilization, immunofluorescence) converging on the same six-TM topology model\",\n      \"pmids\": [\"30959108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LPIAT1/MBOAT7 is the enzyme responsible for incorporating arachidonic acid (AA) into phosphatidylinositol (PI) in mammals. Lpiat1-knockout mice show near-complete loss of LPIAT activity with arachidonoyl-CoA, reduced AA in PI and PI-phosphates, cortical atrophy, hippocampal atrophy, disordered cortical lamination, delayed neuronal migration, and reduced neurite outgrowth in vitro.\",\n      \"method\": \"Gene knockout (Lpiat1−/− mice), in vitro LPIAT activity assay, lipidomics, immunohistochemistry, neurite outgrowth assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — combined enzymatic activity measurement, lipidomics, and in vivo/in vitro phenotypic analysis in knockout mice\",\n      \"pmids\": [\"23097495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LPIAT1/MBOAT7 plays a non-redundant role in maintaining physiological levels of PtdIns and PtdInsP2 through an active deacylation/reacylation (Lands) cycle. Knockout mice show a 26–44% reduction in total PtdIns and PtdInsP2 in brain and liver, a 300–525% increase in C18:0 lyso-PtdIns, and a selective reduction of C38:4 (arachidonoyl-containing) species, with no compensation from other molecular species.\",\n      \"method\": \"Gene knockout mouse (LPIAT1−/−), LC-ESI/MS lipidomics of liver and brain\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive LC-MS lipidomics in knockout tissue, replicated across two tissue types, independent of the 2012 study\",\n      \"pmids\": [\"23472195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mboat7 loss of function in mice (but not Tmc4 loss) is sufficient to promote NAFLD progression under high-fat diet. Mboat7 knockdown leads to accumulation of lysophosphatidylinositol (LPI) substrates. Direct hepatic administration of LPI promotes inflammatory and fibrotic transcriptional changes in an Mboat7-dependent manner, establishing LPI accumulation as the mechanistic driver of liver disease.\",\n      \"method\": \"Antisense oligonucleotide (ASO) knockdown in mice, hepatic LPI administration, transcriptional profiling, lipidomics\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss-of-function with genetic specificity (Mboat7 vs Tmc4), direct LPI administration rescue/phenocopy experiment, multiple readouts\",\n      \"pmids\": [\"31621579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hepatocyte-specific Lpiat1/MBOAT7 knockout mice develop spontaneous hepatic steatosis and fibrosis on high-fat diet. The mechanism involves increased PI turnover: reduced PI acyl-chain remodeling stimulates both PI synthesis and breakdown; PI degradation by phospholipase C produces diacylglycerol (DAG), a precursor to triglyceride synthesis, fueling steatosis through this non-canonical pathway.\",\n      \"method\": \"Hepatocyte-specific Lpiat1 knockout mouse, CRISPR-Cas9 and siRNA depletion in human hepatic cells, radiolabeled glycerol/fatty acid metabolic flux, LC-ESI-MS lipidomics, liver spheroid model\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple model systems (mouse KO, human cell CRISPR, spheroids), metabolic flux tracing, and lipidomics establishing pathway mechanism\",\n      \"pmids\": [\"32253259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hepatocyte-specific deletion of Mboat7 causes spontaneous steatosis characterized by increased hepatic cholesterol ester content and, on a fibrogenic diet, increased fibrosis independent of inflammation. Lipidomics of knockout mice and human rs641738TT carriers both show increased total lysophosphatidylinositol levels and similar alterations in LPI/PI subspecies, indicating inflammation-independent lipid-signaling-mediated fibrogenesis.\",\n      \"method\": \"Hepatocyte-specific Mboat7 knockout mouse (Mboat7Δhep), picrosirius staining, hydroxyproline quantification, RNA sequencing, flow cytometry, LC-MS lipidomics of mouse liver and human liver biopsies\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent model systems (mouse KO and human genotyped liver biopsies) with converging lipidomic evidence, multiple orthogonal methods\",\n      \"pmids\": [\"32591434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hepatic deletion of Mboat7 (Mboat7 LSKO mice) causes fatty liver associated with activation of SREBP-1c and increased de novo lipogenesis. Lipidomics showed selective reduction of 20-carbon PUFA-containing phosphatidylinositols. Co-deletion of SREBP cleavage-activating protein (Scap) with Mboat7 normalized hepatic triglycerides, establishing that increased SREBP-1c processing is required for Mboat7 loss-induced steatosis.\",\n      \"method\": \"Liver-specific Mboat7 knockout mice, compound Mboat7/Scap double-KO, LC-MS lipidomics, gene expression analysis\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by double-KO rescue experiment, supported by lipidomics and gene expression, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32859645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hyperinsulinemia down-regulates hepatic MBOAT7 expression, contributing to steatosis. MBOAT7 deletion in hepatocytes reduces arachidonic acid incorporation into phosphatidylinositol, causes accumulation of saturated triglycerides, enhances lipogenesis, and upregulates fatty acid transporter FATP1. FATP1 deletion rescues the steatosis phenotype, placing FATP1 downstream of MBOAT7 loss.\",\n      \"method\": \"CRISPR/Cas9 knockout in HepG2 cells, antisense oligonucleotide silencing in C57Bl/6 mice, siRNA, lipid mass spectrometry, FATP1 rescue experiment\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by FATP1 deletion rescue, multiple model systems (in vivo ASO + in vitro CRISPR), lipidomic confirmation\",\n      \"pmids\": [\"32058943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MMD (a Golgi-resident scaffold protein) physically interacts with both ACSL4 and MBOAT7, two enzymes that catalyze sequential steps to incorporate arachidonic acid (AA) into phosphatidylinositol (PI). MMD promotes ferroptosis susceptibility in ovarian and renal carcinoma cells in an ACSL4- and MBOAT7-dependent manner by increasing flux of AA into PI, elevating AA-PI and other AA-containing phospholipid species.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP) of MMD with ACSL4 and MBOAT7, genome editing (MBOAT7 KO), lipidomics, ferroptosis cell death assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP establishing ternary complex, supported by KO lipidomics and functional ferroptosis readout, single lab\",\n      \"pmids\": [\"37691145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ACSL3 channels arachidonic acid (AA) into phosphatidylinositols to provide LPIAT1/MBOAT7 with an AA pool to sustain elevated prostaglandin synthesis in non-small cell lung cancer. LPIAT1 knockdown suppresses proliferation, anchorage-independent growth, and in vivo tumorigenesis in KrasG12D-driven lung cancer models, establishing an ACSL3-LPIAT1 signaling axis for prostaglandin production.\",\n      \"method\": \"siRNA knockdown of LPIAT1 in lung cancer cell lines, KrasG12D mouse models, proliferation and anchorage-independent growth assays, in vivo tumorigenesis assay, lipidomics\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular pathway placement (ACSL3→LPIAT1→AA-PI→prostaglandins), in vitro and in vivo phenotypes, single lab\",\n      \"pmids\": [\"32034305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MBOAT7 acts as a negative regulator of toll-like receptor (TLR) signaling in macrophages. MBOAT7 deficiency alters membrane phospholipid composition, redistributing arachidonic acid toward proinflammatory eicosanoids, inducing ER stress, mitochondrial dysfunction, and remodeling of the inflammatory-related chromatin landscape, culminating in enhanced macrophage TLR responses. Activation of MBOAT7 reverses these effects.\",\n      \"method\": \"MBOAT7 knockdown/activation in macrophages, phospholipidomics, eicosanoid profiling, ER stress markers, mitochondrial function assays, ATAC-seq chromatin accessibility profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal mechanistic readouts (lipidomics, eicosanoids, ER stress, chromatin) in macrophage loss/gain-of-function, single lab\",\n      \"pmids\": [\"36473860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hepatocyte-specific (but not myeloid-specific) deletion of Mboat7 exacerbates ethanol-induced liver injury. Lipidomic profiling revealed increased endosomal/lysosomal lipids (bis-monoacylglycerophosphate, phosphatidylglycerols) in ethanol-exposed Mboat7-HSKO mice. Mechanistically, Mboat7 loss impairs TFEB-mediated lysosomal biogenesis and causes autophagosome accumulation, identifying lysosomal lipid homeostasis dysregulation as a key driver of alcohol-associated liver disease.\",\n      \"method\": \"Hepatocyte-specific and myeloid-specific Mboat7 conditional knockout mice, lipidomics, autophagic flux assays, TFEB localization/activity assays, liver injury markers\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type specificity established by parallel hepatocyte vs. myeloid KO, comprehensive lipidomics, autophagic flux mechanistic dissection, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38648183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Adipocyte-specific genetic deletion of Mboat7 promotes hyperinsulinemia, systemic insulin resistance, and mild fatty liver. Unlike in the liver, MBOAT7 is the major source of arachidonic acid-containing PI pools in adipose tissue. Adipocyte MBOAT7-driven PI biosynthesis is closely linked to diet-induced hyperinsulinemia and insulin resistance.\",\n      \"method\": \"Adipocyte-specific Mboat7 knockout mice (adiponectin-Cre), hepatocyte-specific Mboat7 knockout mice (albumin-Cre), metabolic phenotyping, lipidomics of adipose tissue and liver\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-autonomous roles established by parallel tissue-specific KOs, lipidomics across tissues, multiple metabolic phenotype readouts\",\n      \"pmids\": [\"36806709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MBOAT7 restoration in MASH mice lowers hepatocyte TAZ (WWTR1), and hepatocyte MBOAT7 silencing enhances TAZ upregulation. Changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH), establishing a novel MBOAT7→phospholipid→cholesterol trafficking→TAZ→IHH profibrotic axis.\",\n      \"method\": \"AAV-mediated MBOAT7 restoration in MASH mice, hepatocyte MBOAT7 silencing, TAZ/IHH expression analysis, cholesterol trafficking assays, human liver biopsy analysis\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in vivo with defined pathway placement (MBOAT7→phospholipid→cholesterol→TAZ→IHH), validated in human tissue, single lab\",\n      \"pmids\": [\"38776184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mboat7 deficiency impairs indirect neurogenesis in the developing neocortex by compromising radial glial cell (RGC) integrity, resulting in decreased proliferation, impaired differentiation into intermediate progenitor cells, and increased apoptosis. These defects were preceded by Golgi apparatus rounding and reduced apical E-cadherin expression. The Mboat7-deficient cortex displayed reduced PI(4,5)P2 levels, and pharmacological inhibition of PI(4,5)P2 synthesis recapitulated Golgi rounding, placing PI(4,5)P2 reduction downstream of MBOAT7 loss as the cause of RGC dysfunction.\",\n      \"method\": \"Mboat7 knockout mice, immunohistochemistry of RGC markers, PI(4,5)P2 measurement, pharmacological PI(4,5)P2 synthesis inhibition, Golgi morphology analysis, E-cadherin localization\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mouse KO with cellular phenotype + pharmacological epistasis establishing PI(4,5)P2 as mechanistic link, single lab\",\n      \"pmids\": [\"41488780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mboat7 loss in vivo results in massive accumulation of lysophosphatidylinositol (LPI) and hyperactive mTOR signaling. Inhibiting mTOR signaling with rapamycin rescued neuronal migration defects in Mboat7 knockout mice, establishing that MBOAT7-driven polyunsaturated PI synthesis suppresses mTOR activity to enable proper cortical neuronal migration.\",\n      \"method\": \"Mboat7 knockout mice, LC-MS/MS lipidomics of mouse brain and human neuron cultures during neurodevelopment, mTOR pathway activity assays, mTOR inhibitor (rapamycin) rescue of migration defects\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological rescue (rapamycin) of genetic KO phenotype establishes mTOR epistasis; supported by comprehensive lipidomics in both mouse and human models\",\n      \"pmids\": [\"39742503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Under physiological conditions, MBOAT7 interacts with CDS2 in the ER to maintain lipid metabolic homeostasis. Disruption of this interaction (CDS2 knockdown or loss of function) triggers an adaptive response in which MBOAT7 translocates from the ER to ER–lipid droplet (LD) contact sites in a RAB1-dependent manner. At ER-LD contacts, MBOAT7 inhibits DGAT2-mediated LD growth and promotes lipolysis.\",\n      \"method\": \"Co-immunoprecipitation (CDS2-MBOAT7 interaction), CDS2 knockdown, live-cell imaging of MBOAT7 subcellular relocalization, RAB1 dependence assay, DGAT2 activity and LD size assays, lipolysis measurements\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP plus live imaging and functional LD/lipolysis readouts establish novel mechanism, but preprint, single lab, not yet peer reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.08.26.672501\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Genetic deletion of MBOAT7 in clear cell renal cell carcinoma (ccRCC) cells decreases proliferation, induces cell cycle arrest, and prevents tumor formation in vivo. RNAseq of MBOAT7-knockout cells identified alterations in cell migration and extracellular matrix organization that were validated functionally in migration assays. MBOAT7 expression increases with tumor grade in human ccRCC samples.\",\n      \"method\": \"CRISPR/Cas9 knockout in ccRCC cell lines, proliferation assays, cell cycle analysis, in vivo xenograft assay, RNAseq, migration assays, shotgun lipidomics of human ccRCC tumors\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome editing with multiple cellular and in vivo phenotypic readouts plus lipidomics, single lab\",\n      \"pmids\": [\"32180553\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MBOAT7 (LPIAT1) is a multispanning integral ER/endomembrane acyltransferase with six transmembrane domains and a lumenal catalytic dyad (Asn-321/His-356) that preferentially transfers polyunsaturated fatty acids—especially arachidonic acid (20:4)—from arachidonoyl-CoA to lysophosphatidylinositol (LPI) to produce arachidonic acid-enriched phosphatidylinositol (PI); cryo-EM structure reveals a twisted tunnel allowing substrate access from cytosolic and lumenal sides with N-terminal residues conferring headgroup selectivity; loss of MBOAT7 function causes LPI accumulation and reduced PI/PI-phosphate pools, which in the liver drives steatosis via a PI→DAG→TG metabolic flux (phospholipase C-mediated) and SREBP-1c activation, and fibrosis via a cholesterol trafficking→TAZ→IHH profibrotic axis; in the brain, loss reduces PI(4,5)P2 levels, impairs radial glial cell integrity and cortical neuronal migration through hyperactivation of mTOR signaling; in adipose tissue MBOAT7-driven PI synthesis controls systemic insulin sensitivity; in macrophages MBOAT7 negatively regulates TLR signaling by limiting free arachidonic acid availability for proinflammatory eicosanoid synthesis; and a physical complex with CDS2 in the ER maintains homeostasis, while RAB1-dependent redistribution to ER–lipid droplet contacts inhibits DGAT2-mediated lipid droplet growth.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MBOAT7 (LPIAT1) is the membrane O-acyltransferase that selectively incorporates polyunsaturated fatty acids—principally arachidonic acid—into phosphatidylinositol, acting as the reacylation arm of a Lands-cycle remodeling pathway that sets the cellular pools of arachidonoyl-PI and downstream phosphoinositides [#1, #3, #4]. It is a six-transmembrane integral endomembrane protein with a lumenally oriented catalytic dyad (Asn-321/His-356) whose mutation abolishes activity; cryo-EM shows arachidonoyl-CoA and lyso-PI entering the catalytic center through a twisted tunnel from the cytosolic and lumenal sides, with N-terminal lumenal residues dictating phospholipid headgroup selectivity [#0, #1, #2]. Loss of MBOAT7 causes accumulation of lysophosphatidylinositol and depletion of arachidonoyl-PI and PI-phosphate species, and this lipid imbalance is the proximal driver of its disease phenotypes [#4, #5, #7]. In the liver, MBOAT7 deficiency promotes steatosis and fibrosis through several convergent routes: increased PI turnover feeding a phospholipase C-derived DAG→triglyceride flux, SREBP-1c activation (rescued by Scap co-deletion), FATP1 upregulation (rescued by FATP1 deletion), and a cholesterol-trafficking→TAZ→Indian hedgehog profibrotic axis, while hepatocyte-specific loss also impairs TFEB-mediated lysosomal biogenesis to worsen alcohol-associated injury [#6, #8, #9, #13, #15]. Beyond the liver, MBOAT7-driven PI synthesis governs systemic insulin sensitivity in adipose tissue [#14], limits free arachidonic acid available for proinflammatory eicosanoid production to restrain macrophage TLR signaling [#12], and in the developing neocortex maintains PI(4,5)P2 levels and suppresses mTOR signaling to support radial glial integrity and cortical neuronal migration [#16, #17]. MBOAT7 forms an ER complex with CDS2 and, in cancer contexts, channels arachidonic acid into PI to support prostaglandin synthesis, tumor proliferation, and ACSL4/MMD-dependent ferroptosis susceptibility [#10, #11, #18, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the in vivo enzymatic identity of MBOAT7 as the mammalian arachidonate-incorporating enzyme for PI and linked its loss to a neurodevelopmental phenotype.\",\n      \"evidence\": \"Lpiat1-knockout mice with in vitro LPIAT activity assays, lipidomics, and cortical histology\",\n      \"pmids\": [\"23097495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic residues not yet defined\", \"Structural basis of substrate selectivity unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that MBOAT7 maintains physiological PI and PIP2 pools through a non-redundant deacylation/reacylation Lands cycle, with no compensation from other species.\",\n      \"evidence\": \"LC-ESI/MS lipidomics of liver and brain from LPIAT1-knockout mice\",\n      \"pmids\": [\"23472195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific consequences of pool depletion not yet dissected\", \"Downstream signaling effects not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the six-transmembrane topology and lumenal orientation of the catalytic dyad, framing how substrate access occurs across the membrane.\",\n      \"evidence\": \"FPP assay, selective permeabilization, immunofluorescence, and in silico topology prediction\",\n      \"pmids\": [\"30959108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure not yet resolved\", \"Mechanism of substrate channeling unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that LPI substrate accumulation, not loss of product per se, is the mechanistic driver of MBOAT7-associated liver disease, with genetic specificity over neighboring TMC4.\",\n      \"evidence\": \"ASO knockdown in mice, direct hepatic LPI administration, transcriptional profiling, lipidomics\",\n      \"pmids\": [\"31621579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"LPI receptor/effector mediating inflammatory transcription not identified\", \"Link to fibrosis mechanism not yet resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Dissected multiple convergent hepatic mechanisms by which MBOAT7 loss drives steatosis and fibrosis—PI turnover→DAG→TG flux, FATP1 upregulation, and cholesterol-ester accumulation—across mouse, human cell, and human biopsy systems.\",\n      \"evidence\": \"Hepatocyte-specific knockout mice, CRISPR/siRNA in human hepatic cells, metabolic flux tracing, lipidomics, FATP1 rescue, genotyped human liver biopsies\",\n      \"pmids\": [\"32253259\", \"32591434\", \"32058943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative quantitative contribution of each route not weighted\", \"Trigger linking PI imbalance to phospholipase C activation unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed MBOAT7 in oncogenic and ferroptotic lipid-signaling contexts, showing AA-PI flux supports prostaglandin synthesis and tumor growth in lung and renal cancers.\",\n      \"evidence\": \"siRNA/CRISPR knockout in lung and ccRCC cell lines, KrasG12D and xenograft mouse models, lipidomics, proliferation/migration assays\",\n      \"pmids\": [\"32034305\", \"32180553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab studies per cancer type\", \"Causal eicosanoid species not fully defined in ccRCC\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided direct biochemical proof of substrate preference and identified the essential catalytic residues by reconstituting purified enzyme activity.\",\n      \"evidence\": \"In vitro acyltransferase assay with purified recombinant WT and N321A/H356A mutant MBOAT7 from Pichia pastoris\",\n      \"pmids\": [\"33513444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetic regulation by membrane environment not addressed\", \"Acyl-CoA donor specificity range not exhaustively mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established SREBP-1c processing as a required node for MBOAT7-loss-induced steatosis via epistasis.\",\n      \"evidence\": \"Liver-specific Mboat7 knockout and Mboat7/Scap double-knockout mice with lipidomics and expression analysis\",\n      \"pmids\": [\"32859645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal linking PI depletion to SREBP-1c activation not identified\", \"Interaction with DAG/FATP1 routes not integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed MBOAT7 restrains innate immune signaling by sequestering arachidonic acid away from proinflammatory eicosanoids in macrophages.\",\n      \"evidence\": \"MBOAT7 knockdown/activation in macrophages, phospholipidomics, eicosanoid profiling, ER stress and mitochondrial assays, ATAC-seq\",\n      \"pmids\": [\"36473860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific TLR adaptor steps affected not defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Delivered an atomic-resolution model explaining dual-sided substrate access and headgroup selectivity, and enabled inhibitor discovery.\",\n      \"evidence\": \"Cryo-EM structure, domain-swap mutagenesis between MBOAT1/5/7, virtual screening, in vitro assay\",\n      \"pmids\": [\"37316513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic transition state not captured\", \"Inhibitor efficacy in vivo not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified physical and functional partners—MMD scaffolding ACSL4/MBOAT7 for ferroptosis, and a distinct adipose-specific metabolic role controlling systemic insulin sensitivity.\",\n      \"evidence\": \"Reciprocal Co-IP with lipidomics/ferroptosis assays (MMD), and adipocyte- vs hepatocyte-specific knockout mice with metabolic phenotyping\",\n      \"pmids\": [\"37691145\", \"36806709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MMD complex stoichiometry/structure unknown\", \"Adipose-to-systemic signaling mediator not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the hepatic disease mechanism to a cholesterol-trafficking→TAZ→IHH profibrotic axis and to TFEB-dependent lysosomal homeostasis in alcohol-associated injury.\",\n      \"evidence\": \"AAV MBOAT7 restoration and silencing in MASH mice, hepatocyte vs myeloid conditional knockouts, TAZ/IHH and TFEB/autophagy assays, human biopsies\",\n      \"pmids\": [\"38776184\", \"38648183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link from phospholipid change to cholesterol trafficking unresolved\", \"How PI imbalance impairs TFEB activation unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the neurodevelopmental mechanism: MBOAT7-driven PI synthesis sustains PI(4,5)P2 and suppresses mTOR to maintain radial glial integrity and enable cortical neuronal migration.\",\n      \"evidence\": \"Mboat7 knockout mice with PI(4,5)P2 measurement, pharmacological PI(4,5)P2 inhibition, and rapamycin rescue of migration defects; lipidomics in mouse and human neurons\",\n      \"pmids\": [\"41488780\", \"39742503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LPI accumulation activates mTOR mechanistically unknown\", \"Link between PI(4,5)P2 loss and Golgi rounding not molecularly defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Described a CDS2-anchored ER homeostatic interaction and RAB1-dependent redistribution of MBOAT7 to ER–lipid droplet contacts that restrains DGAT2-mediated droplet growth.\",\n      \"evidence\": \"Co-IP, CDS2 knockdown, live-cell relocalization imaging, RAB1 dependence and DGAT2/lipolysis assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.08.26.672501\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab, not peer reviewed\", \"Structural basis of CDS2 interaction and the relocalization trigger undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single PI-remodeling enzyme integrates its diverse tissue-specific outputs—SREBP-1c, TAZ/IHH, mTOR, TLR, insulin signaling—into a unified lipid-signaling logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model connecting LPI/PI pool changes to the distinct downstream effectors across tissues\", \"Direct LPI sensor/effector not identified\", \"In vivo therapeutic targeting of the enzyme untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 18]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 4, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CDS2\", \"MMD\", \"ACSL4\", \"ACSL3\", \"DGAT2\", \"RAB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}