**2. Ferroptosis**

Ferroptosis is a particular form of cell death that is induced by lipid hydroperoxides derived from the oxidation of reactive species generated by free iron. Cell death in ferroptosis involves three main factors: increased free intracellular iron, depletion of the redox glutathione/GPx4/system xc− and the oxidation of membrane PUFAs [16–18] (Figure 1).

**Figure 1.** Ferroptosis pathway. Ferroptosis can be initiated through transferrin endocytosis linked to transferrin receptor 1 (TFR1). After endocytosis, ferric iron is released from the Transferrin–TRF1 complex and is reduced to ferrous iron (Fe2+). Fe2<sup>+</sup> can be stored in ferritin or remain in the cytoplasm as a labile iron Pool (LIP). The LIP is composed mainly of Fe2+, which through Fenton reaction generates species such as: the hydroxyl radical that reacts with membrane lipids, providing the lipid peroxidation of arachidonic acid (AA) or adrenic acid (AdA). Lipid peroxidation can also occur via enzyme. However, it is necessary for the free polyunsaturated fatty acids (PUFAs) to be esterified as membrane PUFA by the enzymes ACSL4 and LPCAT3, forming arachidonic or adrenic acids esterified in phosphatidyl ethanolamine (PE-AA/PE-AdA). Dioxigenation by 15-LOX generates PE-AA/AdA-OOH, which reacts with other membrane lipids, forming pores in the lipid bilayer, destabilizing it and then rupturing the membrane. Ferroptosis is inhibited by GPx4, which converts PE-AA/AdA-OOH to alcohol and water. This reaction occurs through the use of glutathione (GSH) as a substrate. GSH synthesis occurs via the entry of cystine into the cell by system xc−.
