Journal Article

Activation of GSDME by all- trans -retinal increases sensitivity to photoreceptor ferroptosis

Chen, Yuling, Li, Shiying, Yang, Bo, Yang, Kunhuan, Han, Jiahuai, Wu, Yalin, Xi, Ruitong, Chen, Jingmeng

2025

Overview

Impaired clearance of all- -retinal (atRAL) due to visual cycle dysfunction contributes to photoreceptor atrophy, a key pathological hallmark of Stargardt disease type 1 (STGD1) and dry age-related macular degeneration (AMD). Prior studies have shown that light-induced atRAL accumulation promotes ferroptosis and activates gasdermin E (GSDME) in retinal photoreceptors of mice, a model for STGD1 and dry AMD that exhibits visual cycle disorders. However, the role of GSDME in photoreceptor ferroptosis remains unclear. In this study, we revealed that GSDME activation by atRAL triggered photoreceptor ferroptosis and retinal atrophy via mitochondrial damage and oxidative stress. Knocking out GSDME significantly attenuated light-induced photoreceptor ferroptosis and retinal degeneration in mice. Moreover, deleting the gene in photoreceptor cells prevented atRAL-induced ferroptosis by inhibiting mitochondrial reactive oxygen species (mitoROS) production, iron overload, and lipid peroxidation. Notably, treatment with the mitoROS scavenger MitoTEMPO mitigated ferroptosis in atRAL-loaded photoreceptor cells and dramatically relieved photoreceptor ferroptosis and retinal degeneration in light-exposed mice. We found that both GSDME elimination and MitoTEMPO treatment repressed atRAL-induced photoreceptor ferroptosis and retinal atrophy by inactivating the mitoROS-induced oxidative stress. In conclusion, GSDME-mediated photoreceptor ferroptosis is crucial for inducing structural and functional damage of the retina in retinopathies caused by atRAL accumulation, thereby providing new therapeutic insights for the prevention and treatment of STGD1 and dry AMD.

• Publisher: Ivyspring International Publisher
• Subject: Animals / ATP-Binding Cassette Transporters / Ferroptosis - drug effects / Ferroptosis - genetics / Ferroptosis - physiology / Lipid Peroxidation / Macular Degeneration - metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Mitochondria - metabolism / Oxidative Stress / Photoreceptor Cells, Vertebrate - metabolism / Reactive Oxygen Species - metabolism / Research Paper / Retinal Degeneration - metabolism / Retinaldehyde - metabolism / Retinaldehyde - pharmacology