Figure 1.

Schematic representation of the mechanism of ferroptosis. Ferroptosis is an iron-dependent form of regulated cell death mediated by lipid peroxidation of cellular membranes. Fe³⁺ imported through the transferrin receptor is converted to Fe²⁺ in endosomes and released from endosome by divalent metal transporter 1 (DMT1). Fenton reaction converts Fe²⁺ into Fe³⁺, which induces lipid peroxidation by activating lipoxygenases. Glutathione peroxidase 4 (GPX4) is the major endogenous mechanism to suppress lipid peroxidation. High extracellular concentrations of glutamate inhibit system X_c^-, which imports cystine by exchanging intracellular glutamate for extracellular cystine. Cystine is subsequently converted to cysteine, which generates glutathione (GSH), a cofactor for GPX4. Erastin, glutamate, and sorafenib are inhibitors of system X_c^-; RSL3, ML162 and FIN56 are inhibitors of GPX4.