Protection against ferroptosis through maintaining homeostasis of docosahexaenoate-containing phospholipids

Although polyunsaturated phospholipids are vital for cellular functions, their overaccumulation renders cells vulnerable to ferroptosis. It remains unclear how cells exposed to excess polyunsaturated fatty acids (PUFAs) prevent their over-incorporation into phospholipids. Here, we identified a mechanism by which ubiquitin regulatory X domain-containing protein 8 (UBXD8), a fatty acid (FA)-interacting protein, prevents overaccumulation of phospholipids containing docosahexaenoate (DHA), one of the most abundant PUFAs in mammalian cells. UBXD8 binds to and activates 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), which specifically incorporates DHA into phospholipids. Thus, cultured cells and mouse livers deficient in UBXD8 were resistant to ferroptosis because of reduced production of DHA-containing phospholipids. Excess unsaturated FAs, including DHA, through their interaction with UBXD8, disrupt the UBXD8/AGPAT3 complex, thereby inhibiting AGPAT3-catalyzed synthesis of DHA-containing phospholipids. This FA-sensing mechanism prevents overaccumulation of DHA-containing phospholipids in cells exposed to excess DHA, thus reducing the ferroptotic potency of DHA, a property that might contribute to the health benefits of this ω-3 PUFA.