Shaojie Cui, Jin Ye
Ferroptosis is a form of regulated cell death driven by iron-dependent peroxidation of polyunsaturated phospholipids. The susceptibility of cells to ferroptosis is often strongly shaped by lipid metabolic pathways that determine the abundance, distribution, and redox reactivity of polyunsaturated phospholipids. Enzymes that activate and incorporate polyunsaturated fatty acids into phospholipids generate the substrates whose peroxidation causes ferroptosis, thereby sensitizing cells to ferroptosis. In contrast, synthesis of monounsaturated phospholipids and the presence of lipid-soluble antioxidants limit the accumulation of phospholipid peroxides, thereby protecting cells from ferroptosis. Thus, different tissues may display characteristic ferroptotic responses caused by their unique lipid composition and antioxidant capacity. This review summarizes the metabolic foundations that determine the susceptibility of cells to ferroptosis and discusses the possibility of treating human diseases by modulating cellular sensitivity to ferroptosis.