Ferroptosis: An Overview and Regulatory Mechanisms

Abstract

Ferroptosis is a regulated form of cell death driven by iron-mediated lipid peroxidation. Its execution is initiated by the peroxidation of polyunsaturated fatty acid–containing phospholipids, ultimately leading to membrane rupture. Cells possess multiple defense systems to suppress ferroptosis. The cystine/GSH/GPX4 axis detoxifies and reduces lipid hydroperoxides, whereas several GPX4-independent pathways—such as the FSP1–CoQ10 pathway, the GCH1–BH4 pathway, and the vitamin K cycle—suppress ferroptosis by scavenging lipid radicals and preventing propagation of lipid peroxidation. In addition, endogenous antioxidants including vitamin E, squalene, and 7-dehydrocholesterol also contribute to ferroptosis suppression. Beyond antioxidant defenses, factors such as membrane phospholipid composition and iron homeostasis also determine cellular susceptibility to ferroptosis. Elucidating these regulatory mechanisms provides fundamental insight into ferroptosis biology and also highlights promising therapeutic target against ferroptosis-associated disease conditions, such as cancer, neurodegeneration, and acute organ injuries.

graphical abstract