Positive and Negative Regulation of Ferroptosis and Its Role in Maintaining Metabolic and Redox Homeostasis

Figure 2

Regulation of ferroptosis by amino acid, lipid, and iron metabolism. The initiation and execution of ferroptosis are regulated by the metabolism of amino acid, lipid, and iron. The three hallmarks of ferroptosis are the presence of polyunsaturated fatty acid- (PUFA-) acylated phospholipids (PLs), redox-active iron, and loss in lipid peroxide repair. System xc− imports cystine, which gets reduced to cysteine to synthesize glutathione. GPX4 carries out the elimination of lipid peroxides by utilizing glutathione as a necessary cofactor. Transferrin and transferrin receptors are required for ferroptosis which import iron from the extracellular environment. Iron is essentially required for the accumulation of lipid peroxides. Stored Fe(III) in ferritin is retrieved by autophagy, and also, heme can be degraded by heme oxygenases (HOs) to recover Fe(II).