Iron-dependent reactive oxygen species generation and oxidative stress pathway

The iron-dependent reactive oxygen species (ROS) generation and oxidative stress pathway describes the process by which labile iron catalyzes the formation of toxic free radicals, primarily through the Fenton and Haber-Weiss reactions (Winterbourn, 1995, Toxicology Letters; Koppenol & Hider, 2019, Free Radical Biology and Medicine). In this pathway, ferrous iron (Fe2+) reacts with hydrogen peroxide to produce hydroxyl radicals, which are highly reactive and cause oxidative damage to DNA, proteins, and lipids (Koppenol & Hider, 2019). A critical consequence of this process is lipid peroxidation, which, if unchecked by antioxidant systems like glutathione peroxidase 4 (GPX4), leads to ferroptosis, a distinct form of regulated cell death (Dixon et al., 2012, Cell). This pathway is frequently dysregulated in diseases such as Parkinson's and Alzheimer's, where iron accumulation contributes to neuronal loss, as well as in various cancers where cells may become hypersensitive to iron-mediated damage (Stockwell et al., 2017, Cell). Pharmacological intervention typically involves the use of iron chelators to reduce the labile iron pool or small molecules that either inhibit or induce ferroptosis depending on the therapeutic goal (Mobarra et al., 2016, International Journal of Hematology-Oncology and Stem Cell Research). Consequently, this pathway represents a complex network of metabolic and redox reactions rather than a single protein target, requiring a systems-biology approach to therapeutic development.

Other names

Fenton reaction pathwayIron-mediated oxidative stressFerroptosis pathwayHaber-Weiss reactionLabile iron pool-mediated ROS generation

Iron chelation to sequester catalytic iron, inhibition of lipid peroxidation, modulation of glutathione peroxidase 4 activity, and induction or inhibition of ferroptosis.