A tale of two lipids: Lipid unsaturation commands ferroptosis sensitivity

Membrane lipids play important roles in the regulation of cell fate, including the execution of ferroptosis. Ferroptosis is a non-apoptotic cell death mechanism defined by iron-dependent membrane lipid peroxidation. Phospholipids containing polyunsaturated fatty acids (PUFAs) are highly vulnerable to peroxidation and are essential for ferroptosis execution. By contrast, the incorporation of less oxidizable monounsaturated fatty acids (MUFAs) in membrane phospholipids protects cells from ferroptosis. The enzymes and pathways that govern PUFA and MUFA metabolism therefore play a critical role in determining cellular sensitivity to ferroptosis. Here, we review three lipid metabolic processes-fatty acid biosynthesis, ether lipid biosynthesis, and phospholipid remodeling-that can govern ferroptosis sensitivity by regulating the balance of PUFAs and MUFAs in membrane phospholipids.

Automated summary

Membrane lipids play important roles in the regulation of cell fate, especially in the execution of iron-dependent cell death mechanism called ferroptosis. Polyunsaturated fatty acids (PUFAs) in phospholipids are susceptible to peroxidation and are necessary for ferroptosis, whereas the inclusion of less oxidizable monounsaturated fatty acids (MUFAs) in membrane phospholipids protects cells from ferroptosis. Enzymes and pathways controlling PUFA and MUFA metabolism are crucial in determining cellular sensitivity to ferroptosis. In this review, we focus on three lipid metabolic processes-fatty acid biosynthesis, ether lipid biosynthesis, and phospholipid remodeling-that can regulate the balance of PUFAs and MUFAs in membrane phospholipids, thus affecting ferroptosis sensitivity.