Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis.

Phospholipids containing a single polyunsaturated fatty acyl tail (PL-PUFAs) are considered the driving force behind ferroptosis, whereas phospholipids with diacyl-PUFA tails (PL-PUFAs) have been rarely characterized. Dietary lipids modulate ferroptosis, but the mechanisms governing lipid metabolism and ferroptosis sensitivity are not well understood. Our research revealed a significant accumulation of diacyl-PUFA phosphatidylcholines (PC-PUFAs) following fatty acid or phospholipid treatments, correlating with cancer cell sensitivity to ferroptosis. Depletion of PC-PUFAs occurred in aging and Huntington's disease brain tissue, linking it to ferroptosis. Notably, PC-PUFAs interacted with the mitochondrial electron transport chain, generating reactive oxygen species (ROS) for initiating lipid peroxidation. Mitochondria-targeted antioxidants protected cells from PC-PUFA-induced mitochondrial ROS (mtROS), lipid peroxidation, and cell death. These findings reveal a critical role for PC-PUFAs in controlling mitochondria homeostasis and ferroptosis in various contexts and explain the ferroptosis-modulating mechanisms of free fatty acids. PC-PUFAs may serve as diagnostic and therapeutic targets for modulating ferroptosis.