Redox and ferroptosis machinery

The "Redox and ferroptosis machinery" refers to the integrated network of biochemical pathways that regulate ferroptosis, a form of iron-dependent, non-apoptotic regulated cell death characterized by the accumulation of lipid peroxides (Dixon et al., 2012, Cell). This machinery is centered on the maintenance of lipid redox homeostasis, primarily through the System Xc-/Glutathione/GPX4 axis, which neutralizes lethal lipid hydroperoxides (Stockwell et al., 2017, Cell). Key regulatory components include the cystine/glutamate transporter SLC7A11, the antioxidant enzyme GPX4, and the FSP1-CoQ10-NAD(P)H pathway, which provides an independent defense against lipid peroxidation (Jiang et al., 2021, Nature Reviews Cancer). In clinical development, this machinery is targeted to either induce cell death in therapy-resistant cancers (using GPX4 inhibitors or System Xc- blockers) or to preserve cell viability in neurodegenerative and ischemic conditions (using ferroptosis inhibitors like ferrostatin-1). Because it encompasses a broad suite of enzymes, transporters, and metabolic processes, it represents a therapeutic strategy or pathway rather than a single discrete molecular target.

Other names

Ferroptosis pathwayRedox homeostasis machineryIron-dependent cell death pathwayGPX4-regulated cell death pathway

The machinery is modulated by inhibiting the System Xc- transporter (e.g., erastin, sulfasalazine) to deplete glutathione, or by directly inhibiting glutathione peroxidase 4 (GPX4) (e.g., RSL3, ML162) to allow the accumulation of lethal lipid peroxides (Stockwell et al., 2017, Cell). Conversely, ferroptosis can be inhibited by lipophilic antioxidants (e.g., ferrostatin-1, liproxstatin-1) that scavenge lipid radicals or by iron chelators (e.g., deferoxamine) that limit the Fenton reaction (Dixon et al., 2012, Cell).