Ferroptosis-regulating pathway

The ferroptosis-regulating pathway is a distinct form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels (Dixon et al., 2012; Stockwell et al., 2017). Unlike apoptosis, it does not involve caspases or DNA fragmentation but is instead driven by the oxidative destruction of cellular membranes (Dixon et al., 2012). The pathway is primarily governed by the activity of glutathione peroxidase 4 (GPX4), which utilizes reduced glutathione to neutralize lipid peroxides (Stockwell et al., 2017; Jiang et al., 2021). Inhibition of GPX4 or the depletion of its substrate via the cystine/glutamate antiporter (System Xc-) triggers the ferroptotic cascade (Dixon et al., 2012; Jiang et al., 2021). This pathway plays a pivotal role in tumor suppression, as many therapy-resistant cancer cells are uniquely sensitive to ferroptosis induction (Jiang et al., 2021; Hassannia et al., 2019). Conversely, the pathway is implicated in the pathogenesis of neurodegenerative diseases and ischemia-reperfusion injury, where excessive ferroptosis leads to tissue loss (Stockwell et al., 2017; Hassannia et al., 2019). Pharmacological agents like Erastin and RSL3 are used to induce ferroptosis in research, while small molecules like Ferrostatin-1 act as inhibitors by scavenging lipid radicals (Dixon et al., 2012; Stockwell et al., 2017). Understanding this pathway offers significant therapeutic potential for both oncology and regenerative medicine (Jiang et al., 2021).

Other names

Ferroptosis signaling pathwayFerroptosis pathwayIron-dependent cell death pathway

Modulation of the ferroptosis-regulating pathway occurs through several distinct mechanisms: induction of ferroptosis via inhibition of the cystine/glutamate antiporter (System Xc-) or direct inhibition of glutathione peroxidase 4 (GPX4), and inhibition of ferroptosis via the scavenging of lipid peroxyl radicals by lipophilic antioxidants (Dixon et al., 2012; Stockwell et al., 2017).