2. Academic Validation
  3. PHOSPHO1 Suppresses Ferroptosis in Retinal Pigment Epithelial Cells by Reducing the Levels of Phosphatidylethanolamine Molecular Species

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

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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