Ferroptosis regulatory network

The ferroptosis regulatory network is a complex biochemical system that controls a form of regulated cell death characterized by iron-dependent lipid peroxidation (Dixon et al., 2012, Cell). This network integrates several metabolic pathways, including iron metabolism, the biosynthesis of polyunsaturated fatty acid-containing phospholipids, and the glutathione-dependent antioxidant defense system (Stockwell et al., 2017, Cell). At its core, the enzyme glutathione peroxidase 4 (GPX4) serves as a master regulator by neutralizing lipid hydroperoxides that would otherwise cause membrane rupture. In oncology, the network is a target for inducing cell death in therapy-resistant tumors, particularly those with high mesenchymal characteristics (Jiang et al., 2021, Nature Reviews Cancer). Conversely, the inhibition of this network is being investigated as a therapeutic strategy to mitigate tissue damage in neurodegenerative diseases and ischemia-reperfusion injuries (Yan et al., 2021, Communications Biology). Drugs targeting this network range from small-molecule inducers like Erastin to inhibitors like Ferrostatin-1, each acting on specific nodes such as System Xc- or lipid radical scavenging.

Other names

Ferroptosis pathwayIron-dependent cell death signalingFerroptotic cell death

Pharmacological modulation of the ferroptosis regulatory network involves the inhibition of the cystine/glutamate antiporter (System Xc-), direct inactivation of glutathione peroxidase 4 (GPX4), or the depletion of glutathione (GSH) to induce lipid peroxidation (Dixon et al., 2012, Cell). Conversely, ferroptosis inhibitors act by scavenging lipid peroxyl radicals (e.g., Ferrostatin-1) or chelating intracellular iron (e.g., Deferoxamine) to prevent the Fenton reaction and subsequent membrane damage (Stockwell et al., 2017, Cell).