Iron-dependent lipid peroxidation pathway (Ferroptosis)

The iron / lipid peroxidation system, primarily known as the ferroptosis pathway, is a form of regulated cell death driven by the iron-dependent accumulation of lipid hydroperoxides to lethal levels (Dixon et al., 2012, Cell). This process is distinct from apoptosis and is characterized by the loss of lipid peroxide repair activity by glutathione peroxidase 4 (GPX4) and the presence of a labile iron pool that facilitates the production of reactive oxygen species via the Fenton reaction (Stockwell et al., 2017, Cell). In healthy cells, this system is tightly regulated by antioxidant defenses, particularly the System Xc- cystine/glutamate antiporter which provides the building blocks for glutathione synthesis (Jiang et al., 2021, Nature Reviews Cancer). Pathologically, the dysregulation of this system is implicated in various conditions; its overactivation contributes to neurodegenerative diseases, stroke, and organ ischemia-reperfusion injury, while its evasion is a hallmark of certain therapy-resistant cancers (Li et al., 2020, Cell Death & Disease). Therapeutic strategies involve either inhibiting the system using iron chelators (e.g., Deferoxamine) and lipophilic antioxidants (e.g., Ferrostatin-1) to prevent cell loss, or inducing it using small molecules (e.g., Erastin, RSL3) to eliminate malignant cells (Conrad et al., 2021, Nature Reviews Drug Discovery).

Other names

FerroptosisIron-dependent lipid peroxidationLipid peroxidation pathwayIron-mediated cell death

Modulation of iron-dependent lipid hydroperoxide accumulation through GPX4 inhibition, System Xc- blockade, or iron chelation.