Ferroptosis regulatory axis

The Ferroptosis regulatory axis is a complex biochemical network that governs ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation. This axis primarily integrates three metabolic pathways: the System Xc-/glutathione (GSH)/glutathione peroxidase 4 (GPX4) antioxidant defense, iron metabolism, and lipid metabolism involving polyunsaturated fatty acids (PUFAs). GPX4 serves as a central regulator by reducing lipid hydroperoxides to non-toxic lipid alcohols using GSH as a cofactor. Dysregulation of this axis is implicated in various diseases, including cancer, where tumor cells often overexpress defense components to resist ferroptosis, and neurodegenerative or ischemic diseases, where excessive ferroptosis contributes to tissue damage. Pharmacological modulation of the axis involves inducing ferroptosis to kill therapy-resistant cancer cells or inhibiting it to protect against degenerative conditions. Key therapeutic strategies include the use of small-molecule inducers like erastin and RSL3, or inhibitors such as ferrostatin-1 and iron chelators.

Other names

Ferroptosis signaling pathwayFerroptosis pathwayFerroptosis regulatory networkSystem Xc-/GSH/GPX4 axisIron-dependent cell death pathway

The axis is modulated by inducing or inhibiting iron-dependent lipid peroxidation. Inducers typically inhibit antioxidant defenses like System Xc- or GPX4, or promote iron accumulation and lipid oxidation. Inhibitors act as radical-trapping antioxidants, iron chelators, or inhibitors of lipid-processing enzymes like ACSL4.