MBOAT2

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).

1. 2024 Medium

   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

   PMID:39179098

   Open questions at the time

   • 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
2. 2024 Low

   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

   PMID:39594462

   Open questions at the time

   • 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
3. 2025 Medium

   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

   PMID:41093166

   Open questions at the time

   • 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
4. 2025 Low

   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

   PMID:40201699

   Open questions at the time

   • 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
5. 2025 Medium

   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)

   PMID:bio_10.1101_2025.11.02.686003

   Open questions at the time

   • 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

• 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.
• 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