Chen Zhiyang, Zhu Xiaoman, Lu Michael Mingze, Ou Qingjian, Wang Xueying, Zhao Zhenzhen, Shen Qi, Wang Qian, Wang Zhe, Xu Jing-Ying, Jin Caixia, Gao Furong, Wang Juan, Zhang Jingfa, Zhang Jieping, Jin Xiaoliang, Bi Yanlong, Lu Lixia, Xu Guo-Tong, Tian Haibin
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, School of Medicine, Tongji University, Shanghai, 200065, China.
Department of Physiology and Pharmacology, School of Medicine, Tongji University, Shanghai, 200092, China.
Adv Sci (Weinh). 2025 Jul;12(28):e2505359. doi: 10.1002/advs.202505359. Epub 2025 May 21.
Iron-induced lipid peroxidation of phosphatidylethanolamine (PE) species is a key driver of ferroptosis in retinal pigment epithelial (RPE) cells, a process closely associated with age-related macular degeneration (AMD). The previous studies have demonstrated that induced retinal pigment epithelial (iRPE) cells generated by transcription factor-mediated reprogramming exhibit superior therapeutic efficacy in treating AMD. In this study, it is found that these iRPE cells are resistant to ferroptosis and further identified phosphoethanolamine/phosphocholine phosphatase 1 (PHOSPHO1) as a critical regulator underlying ferroptosis resistance. Mechanistically, PHOSPHO1 inhibits ferroptosis through two distinct mechanisms. First, it reduces PE levels in the endoplasmic reticulum, thereby limiting PE-derived lipid peroxidation. Second, it suppresses autophagy and ferritinophagy, leading to a reduction in intracellular free iron accumulation. Experiments using an in vivo rat model confirm that PHOSPHO1 effectively protects RPE cells from ferroptotic damage. These findings highlight PHOSPHO1 as a potential therapeutic target for AMD, providing insights into novel ferroptosis-based intervention strategies.
铁诱导的磷脂酰乙醇胺（PE）种类的脂质过氧化是视网膜色素上皮（RPE）细胞中铁死亡的关键驱动因素，这一过程与年龄相关性黄斑变性（AMD）密切相关。先前的研究表明，通过转录因子介导的重编程产生的诱导性视网膜色素上皮（iRPE）细胞在治疗AMD方面表现出卓越的治疗效果。在本研究中，发现这些iRPE细胞对铁死亡具有抗性，并进一步确定磷酸乙醇胺/磷酸胆碱磷酸酶1（PHOSPHO1）是铁死亡抗性的关键调节因子。从机制上讲，PHOSPHO1通过两种不同的机制抑制铁死亡。首先，它降低内质网中的PE水平，从而限制PE衍生的脂质过氧化。其次，它抑制自噬和铁蛋白自噬，导致细胞内游离铁积累减少。使用体内大鼠模型的实验证实，PHOSPHO1有效地保护RPE细胞免受铁死亡损伤。这些发现突出了PHOSPHO1作为AMD潜在治疗靶点的地位，为基于铁死亡的新型干预策略提供了见解。
