Exposure of A2E to blue light promotes ferroptosis in the retinal pigment epithelium

作者：Bo Yang, Kunhuan Yang, Yuling Chen, Qingjian Li, Jingmeng Chen, Shiying Li, Yalin Wu · 发表于：Cellular & Molecular Biology Letters · 年份：2025 · DOI：10.1186/s11658-025-00700-2 · 被引用次数：30 · 研究领域：Retinal Diseases and Treatments、Ferroptosis and cancer prognosis、Antioxidant Activity and Oxidative Stress

Abstract Background Age-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) is closely related to the etiology of autosomal recessive Stargardt’s disease (STGD1) and dry age-related macular degeneration (AMD). N -retinylidene- N -retinylethanolamine (A2E) is a leading component of RPE lipofuscin that is highly susceptible to blue light. Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by the accumulation of lipid peroxides to a lethal level, which plays an important role in retinal diseases. However, it remains unknown whether A2E functions as a physiological trigger for eliciting blue light-induced ferroptosis of RPE cells. Methods A2E-loaded RPE cells and Abca4 −/− Rdh8 −/− mice were exposed to blue light, respectively. Western blotting, immunofluorescence staining, reactive oxygen species (ROS) staining, intracellular iron staining, lipid peroxidation staining, fundus imaging, optical coherence tomography (OCT), hematoxylin–eosin (HE) staining, and electroretinography (ERG) were utilized to elucidate the role of blue light in A2E induced ferroptosis in the RPE and its potential mechanisms. Results Exposure of A2E to blue light promoted ferroptotic cell death in RPE cells by elevating ferrous ion (Fe 2+ ) levels and inhibiting the solute carrier family 7 membrane 11 (SLC7A11)-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis. GPX4 inactivation and ROS generated by Fe 2+ overload and GSH depletion precipitated lipi...