Ferroptosis in Cerebral Ischemia/Reperfusion Injury: Mechanistic Drivers and Therapeutic Frontiers

Ferroptosis, an iron-dependent cell death pathway driven by lipid peroxidation, critically contributes to cerebral ischemia/reperfusion (I/R) injury. In ischemic stroke, neuronal ferroptosis arises from iron overload and antioxidant system failure. Excessive Fe²⁺ fuels hydroxyl radical production via the Fenton reaction, accelerating lipid peroxidation in PUFA-rich membranes. Concurrently, cysteine depletion and GPX4 inactivation disrupt the GPX4-glutathione antioxidant axis, allowing toxic lipid peroxide accumulation. Enzymes like ACSL4 and LPCAT3 esterify PUFAs into phospholipids, enabling lipoxygenases (LOXs) to generate peroxides, while impaired repair pathways (eg, FSP1-CoQ10) exacerbate damage. Therapeutic strategies target iron chelators (eg, deferoxamine), lipid peroxidation inhibitors (liproxstatin-1), and GPX4 activators to restore redox balance. Targeting propagation mediators (eg, Galectin-13, which reduces SLC7A11 membrane localization) may limit damage spread. Combinatorial therapies addressing iron regulation and lipid peroxidation pathways offer promising neuroprotection against I/R-related neurodegeneration, positioning ferroptosis as a key druggable target.