Figure 4.

Regulation of ferroptosis. Transmembrane system X_C^¯ composed of SLC3A2 and SLC7A11 subunits sustains the glutathione (GSH) homeostasis. GPX4 catalyzes the glutathione-dependent reduction of lipid hydroperoxides (L-OOH) to lipid alcohols (L-OH) that prevents from the formation of highly reactive lipid alkoxy radicals (L-O^•) and induction of ferroptosis. This process can also be prevented by the activity of FSP1, while Fe²⁺ released from ferritin in NCOA4-mediated ferritinophagy accelerates ferroptosis. Several genes encoding ferroptosis-regulating proteins are under transcriptional control of p53 and nuclear factor erythroid 2-related factor 2 (NRF-2). Compounds that inhibit ferroptosis are shown in orange background, and activators of ferroptosis are shown in dark green background. Mechanisms of ferroptosis regulation that have been demonstrated in melanoma are additionally included.