Yang Bo, Yang Kunhuan, Chen Yuling, Li Qingjian, Chen Jingmeng, Li Shiying, Wu Yalin
Department of Ophthalmology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, China.
Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China.
Cell Mol Biol Lett. 2025 Feb 21;30(1):22. doi: 10.1186/s11658-025-00700-2.
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.
A2E-loaded RPE cells and Abca4Rdh8 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.
Exposure of A2E to blue light promoted ferroptotic cell death in RPE cells by elevating ferrous ion (Fe) 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 overload and GSH depletion precipitated lipid peroxidation and subsequent ferroptosis in A2E-containing RPE cells upon exposure to blue light. In addition to GSH supplement, repressing either Fe by deferiprone (DFP) or lipid peroxidation with ferrostatin-1 (Fer-1) significantly protected RPE cells against ferroptosis caused by blue light illumination of A2E. Abca4Rdh8 mice featured by an accelerated deposition of A2E in the RPE is an animal model for STGD1 and dry AMD. It was observed that ferroptosis was indeed present in the RPE of Abca4Rdh8 mice following exposure to blue light. Notably, alleviating ferroptosis by intraperitoneally injected Fer-1 effectively rescued retinal function and ameliorated RPE/photoreceptor degeneration in blue light-exposed Abca4Rdh8 mice.
Our results suggest the importance of blue light in A2E-mediated ferroptosis in the RPE, and deeply broaden the understanding of mechanisms underlying RPE atrophy arising from lipofuscin accumulation in STGD1 and dry AMD.
视网膜色素上皮（RPE）中脂褐素的年龄依赖性积累与常染色体隐性遗传性Stargardt病（STGD1）和干性年龄相关性黄斑变性（AMD）的病因密切相关。N-视黄叉基-N-视黄基乙醇胺（A2E）是RPE脂褐素的主要成分，对蓝光高度敏感。铁死亡是一种铁依赖性的非凋亡性细胞死亡形式，其特征是脂质过氧化物积累到致死水平，在视网膜疾病中起重要作用。然而，A2E是否作为引发蓝光诱导的RPE细胞铁死亡的生理触发因素仍不清楚。
分别将负载A2E的RPE细胞和Abca4Rdh8小鼠暴露于蓝光下。采用蛋白质免疫印迹法、免疫荧光染色、活性氧（ROS）染色、细胞内铁染色、脂质过氧化染色、眼底成像、光学相干断层扫描（OCT）、苏木精-伊红（HE）染色和视网膜电图（ERG）来阐明蓝光在A2E诱导的RPE铁死亡中的作用及其潜在机制。
A2E暴露于蓝光下通过提高亚铁离子（Fe）水平和抑制溶质载体家族7成员11（SLC7A11）-谷胱甘肽（GSH）-谷胱甘肽过氧化物酶4（GPX4）轴促进RPE细胞发生铁死亡。暴露于蓝光下时，GPX4失活以及Fe过载和GSH耗竭产生的ROS促使含A2E的RPE细胞发生脂质过氧化及随后的铁死亡。除了补充GSH外，用去铁酮（DFP）抑制Fe或用铁死亡抑制剂1（Fer-1）抑制脂质过氧化均能显著保护RPE细胞免受A2E蓝光照射引起的铁死亡。Abca4Rdh8小鼠的特征是RPE中A2E沉积加速，是STGD1和干性AMD的动物模型。观察到蓝光照射后，Abca4Rdh8小鼠的RPE中确实存在铁死亡。值得注意的是，腹腔注射Fer-1减轻铁死亡可有效挽救蓝光照射的Abca4Rdh8小鼠的视网膜功能，并改善RPE/光感受器变性。
我们的结果表明蓝光在A2E介导的RPE铁死亡中的重要性，并深入拓展了对STGD1和干性AMD中脂褐素积累导致RPE萎缩的潜在机制的理解。
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