Fig. 3: Overview of the metabolic routes contributing to ferroptosis.

Several metabolic pathways are involved in the regulation of ferroptosis, including: (i) iron-Fenton reaction (black). ROS are produced by the Fenton reaction that is driven by excessive iron, which can be derived from the import of extracellular iron and the supply of intracellular stored iron via ferritinophagy. (ii) GPX4 antioxidant activity (brown and blue). Suppression of lipid peroxidation and ferroptosis occurrence largely depends on GPX4 activity, which relies on GSH and IPP-derived Sec. Cystine import by the amino acid antiporter system \(x_c^ -\) and mevalonate routes are necessary for GSH and IPP production, respectively. Additionally, IPP-derived CoQ inhibits ferroptosis mediated by FSP1 in the cytosol or by DHODH in mitochondria. (iii) Lipid metabolism pathway (green). The oxidation of PUFA and AA is also involved in ferroptosis.