Superoxide Activates Ferroptosis via the Haber‐Weiss Reaction and Enhances Age‐Related Macular Degeneration

Antioxidant decline is crucial to driving age-related macular degeneration (AMD). Ferroptosis, a regulated cell death mediated by iron-dependent hydroxyl radical-catalyzed phospholipid peroxidation through the Fenton reaction, is implicated in various chronic degenerative diseases. Here, we show that superoxide activates ferroptosis in retinal pigment epithelium (RPE) cells via the Haber-Weiss reaction, thereby contributing to dry AMD. We silenced manganese superoxide dismutase (MnSOD/SOD2) in RPE cells and exposed the cells to blue light to induce ferroptosis by increasing superoxide anions. Additionally, MnSOD deficiency triggered the Hsp70-linked ubiquitin-dependent degradation of GPX4, further aggravating ferroptosis. We validated blue light-induced ferroptosis in the RPE layer as a driver of the dry AMD phenotype in Sod2^+/- mice. Consequently, SOD mimetics efficiently protected RPE against phototoxicity by reducing superoxide-activated ferroptosis. Iron chelators or overexpressing GPX4 sufficiently eradicated ferroptosis. The finding reveals that excessive superoxide contributes to phospholipid peroxidation, providing a promising approach for preventing dry AMD by elevating MnSOD to inhibit RPE cell ferroptosis.