Ferroptosis regulatory machinery

The ferroptosis regulatory machinery is a complex network of biochemical pathways and proteins that govern ferroptosis, an iron-dependent form of regulated cell death driven by the lethal accumulation of lipid hydroperoxides (Dixon et al., 2012). This machinery is centered around the maintenance of redox homeostasis, primarily through the System Xc-/Glutathione (GSH)/Glutathione Peroxidase 4 (GPX4) axis, which neutralizes lipid peroxides in cellular membranes (Stockwell et al., 2017). Other critical components include the iron metabolic pathway, which regulates the labile iron pool required for the Fenton reaction, and the lipid metabolic machinery (e.g., ACSL4), which provides the polyunsaturated fatty acids that serve as substrates for peroxidation (Bersuker et al., 2019). Dysregulation of these processes is a hallmark of various pathologies; for instance, cancer cells often upregulate antioxidant defenses to evade ferroptosis, while excessive ferroptotic activity is linked to neurodegeneration and ischemia-reperfusion injury (Li et al., 2020). Therapeutic strategies targeting this machinery involve the use of ferroptosis inducers (FINs) like erastin and RSL3 to treat therapy-resistant tumors, or ferroptosis inhibitors such as ferrostatin-1 and iron chelators to protect tissues from oxidative damage (Tang & Kroemer, 2020). Despite its therapeutic potential, targeting the ferroptosis machinery presents challenges, including the risk of systemic toxicity and the lack of highly specific clinical biomarkers (Chen et al., 2021).

Other names

Ferroptosis signaling pathwayFerroptosis regulatory networkFerroptosis-related proteinsFerroptosis pathway

Modulation of ferroptosis through the inhibition of antioxidant defense systems (e.g., GPX4 or System Xc-), the chelation of catalytic iron, or the prevention of lipid peroxidation using radical-trapping antioxidants.