PHOSPHO1 Suppresses Ferroptosis in Retinal Pigment Epithelial Cells by Reducing the Levels of Phosphatidylethanolamine Molecular Species

  • Adv Sci (Weinh). 2025 Jul;12(28):e2505359. doi: 10.1002/advs.202505359.
Zhiyang Chen  1 ,  Xiaoman Zhu  1 ,  Michael Mingze Lu  1 ,  Qingjian Ou  1  2 ,  Xueying Wang  1 ,  Zhenzhen Zhao  1 ,  Qi Shen  1 ,  Qian Wang  1 ,  Zhe Wang  3 ,  Jing-Ying Xu  1 ,  Caixia Jin  1 ,  Furong Gao  1 ,  Juan Wang  1 ,  Jingfa Zhang  4 ,  Jieping Zhang  1  2 ,  Xiaoliang Jin  5 ,  Yanlong Bi  1 ,  Lixia Lu  1 ,  Guo-Tong Xu  1 ,  Haibin Tian  1  2
Affiliations
  • 1. 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.
  • 2. Department of Physiology and Pharmacology, School of Medicine, Tongji University, Shanghai, 200092, China.
  • 3. Department of Physiology, College of Basic Medical Sciences, Naval Medical University, Shanghai, 200433, China.
  • 4. The International Eye Research Institute of the Chinese University of Hong Kong (Shenzhen), Shenzhen, 518000, China.
  • 5. Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
PMID: 40396905 DOI: 10.1002/advs.202505359
Abstract

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.

Keywords
age‐related macular degeneration; ferroptosis; phosphatidylethanolamine; phosphoethanolamine/phosphocholine phosphatase 1; retinal pigment epithelial cells.
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