Fig. 1: The regulatory pathways of ferroptosis.

Ferroptosis is triggered by the excessive lipid peroxidation (LPO). Cysteine and reduced glutathione (GSH) availability are regulated by cystine-glutamate antiporter system X_c^– or the transsulfuration pathway. The transsulfuration pathway is a metabolic pathway for the production of cysteine (Cys)-containing amino acids and the synthesis of GSH through the interconversion of cysteine and homocysteine. Glutamine can be transported into intracellular places by SLC1A5 transporter, and then converted into glutamate by glutaminase (GLS) to affect the GSH availability. GSH is a key cofactor of GPX4 for clearing lipid peroxides. The suppression of system X_c⁻ by erastin or GPX4 activity by RSL3, which ultimately leads to cell ferroptosis. On the one hand, the peroxidation of PUFAs and excess irons is considered to be an important contributor. Iron uptake via the transferrin receptor-like TFR1 or degradation of ferritin iron stores enhances the labile iron pool, thereby cells are susceptible to ferroptosis via lipid hydroperoxides generation from the Fenton-like reaction. In addition, the mevalonate pathway is also involved in ferroptosis process by generating a series of biomolecules with potential anti-ferroptotic activity such as squalene, coenzyme Q10 (CoQ10), isopentenyl- pyrophosphate (IPP), and farnesyl pyrophosphate (FPP), which in part influences the ferroptosis occurrences. POR cytochrome P450 oxidoreductase, LOX lipoxygenase.