Regulation of ferroptosis by lipid metabolism

Ferroptosis is an iron-dependent lethal mechanism that can be activated in disease and is a proposed target for cancer therapy. Ferroptosis is defined by the overwhelming accumulation of membrane lipid peroxides. Ferroptotic lipid peroxidation is initiated on internal membranes and then appears at the plasma membrane, triggering lethal ion imbalances and membrane permeabilization. Sensitivity to ferroptosis is governed by the levels of peroxidizable polyunsaturated lipids and associated lipid metabolic enzymes. A different network of enzymes and endogenous metabolites restrains lipid peroxidation by interfering with the initiation or propagation of this process. This emerging understanding is informing new approaches to treat disease by modulating lipid metabolism to enhance or inhibit ferroptosis.