Ferroptosis is driven by PUFA-PLs synthesis, lipid peroxidation and iron toxicity. Major defense systems of ferroptosis include the GPX4 antioxidant system, FSP1/ubiquinol (CoQH2), DHODH/CoQH2, GCH1/tetrahydrobiopterin (BH4) systems, monounsaturated fatty acid (MUFA)-PLs synthesis, and the ESCRT-III-mediated membrane repair systems. When ferroptosis-promoting activities significantly surpass the detoxification capabilities provided by the defense systems, a fatal accumulation of lipid peroxides on the cellular membranes ultimately results in membrane rupture and ferroptotic cell death.