MBOAT2

MBOAT2 is a lysophospholipid acyltransferase that remodels membrane phospholipid composition by limiting the incorporation of polyunsaturated fatty acids into phosphatidylcholine while enriching monounsaturated fatty acids, an activity that buffers oxidative stress from lipid peroxidation and thereby suppresses ferroptosis [PMID:bio_10.1101_2025.11.02.686003]. Through this membrane-remodeling function it acts as a protective factor in multiple settings: its induction in activated satellite cells promotes muscle regeneration [PMID:bio_10.1101_2025.11.02.686003], and in neurons it cooperates with oleic acid in a mutually dependent manner to reduce ferroptosis (PMID:39594462). The anti-ferroptotic activity of MBOAT2 is governed by upstream regulators and physical partners — androgen receptor signaling drives MBOAT2 expression to limit neuronal ferroptosis (PMID:40201699), and FERMT1 physically interacts with MBOAT2 to suppress ferroptosis, an effect that requires MBOAT2 and is restored by its overexpression in FERMT1-deficient cells (PMID:41093166). In endothelial cells, gain of MBOAT2 disrupts glycerophospholipid metabolism and triggers endoplasmic reticulum stress-dependent pyroptosis, and endothelium-specific overexpression aggravates atherosclerosis in ApoE-/- mice, a pathway induced by TMAO (PMID:39179098). MBOAT2 overexpression also accelerates proliferation, migration, and cell cycle progression in pancreatic cancer cells (PMID:35571489).

1. 2022 Low

   An initial link between MBOAT2 and cancer cell behavior was established, showing that elevated MBOAT2 can drive proliferation and cell cycle progression.

   Evidence MBOAT2 overexpression with proliferation, migration, and flow cytometry cell-cycle assays in pancreatic cancer cells

   PMID:35571489

   Open questions at the time

   • Single overexpression study without mechanistic dissection of how MBOAT2 enzymatic activity drives CDK2/CCNA2 induction
   • No link to lipid remodeling or ferroptosis in this context
   • Loss-of-function not tested
2. 2024 Medium

   MBOAT2 was implicated as a pathogenic effector in vascular disease, defining a context where its overexpression is harmful rather than protective.

   Evidence AAV endothelium-specific MBOAT2 overexpression in ApoE-/- mice with lipidomics, ER stress, and pyroptosis readouts

   PMID:39179098

   Open questions at the time

   • Molecular link between glycerophospholipid disruption and ER stress not fully mapped
   • Direct enzymatic mechanism in endothelial cells not characterized
   • How TMAO upregulates MBOAT2 transcriptionally is unresolved
3. 2024 Low

   MBOAT2 was tied to neuronal protection through membrane phospholipid remodeling and a dependency on oleic acid.

   Evidence Hypoxia mouse model with HBO therapy, lipidomic analysis, and in vitro MBOAT2/oleic acid manipulation

   PMID:39594462

   Open questions at the time

   • Mutual dependence of oleic acid and MBOAT2 stated but not mechanistically dissected
   • Direct enzymatic assay not performed in this system
   • Single lab
4. 2025 Medium

   The enzymatic identity of MBOAT2 as a lysophospholipid acyltransferase favoring MUFA over PUFA incorporation into PC was established, providing the biochemical basis for its anti-ferroptotic role.

   Evidence Lipidomic profiling and loss/gain-of-function in satellite cells with enzymatic characterization (preprint)

   PMID:bio_10.1101_2025.11.02.686003

   Open questions at the time

   • Preprint, not yet peer-reviewed
   • Substrate specificity and structural basis of acyl-chain selectivity not defined
   • Generalizability beyond muscle regeneration to be confirmed
5. 2025 Medium

   Upstream and physical regulators of MBOAT2 in ferroptosis were identified, placing it downstream of androgen receptor and in complex with FERMT1.

   Evidence AR knockdown in PC12 cells and Co-IP plus reciprocal gain/loss-of-function with erastin/ferrostatin-1 ferroptosis assays in glioma cells

   PMID:40201699 PMID:41093166

   Open questions at the time

   • Whether AR regulates MBOAT2 directly at the transcriptional level is unknown
   • FERMT1-MBOAT2 interaction interface and stoichiometry not defined
   • Single Co-IP without reciprocal/structural validation

• How MBOAT2's single acyltransferase activity produces opposite outcomes — protective anti-ferroptotic remodeling versus pathogenic glycerophospholipid disruption and pyroptosis — across cell types remains unresolved.
• No unifying model reconciling protective versus pathogenic phenotypes
• No structural data on substrate selectivity
• Direct enzymatic kinetics not reported in peer-reviewed work