2. Academic Validation
  3. KIF11 prevents retinal endothelial ferroptosis in familial exudative vitreoretinopathy by inhibiting phosphorylation-driven PRDX1 phase separation

KIF11 prevents retinal endothelial ferroptosis in familial exudative vitreoretinopathy by inhibiting phosphorylation-driven PRDX1 phase separation

  • Nat Commun. 2026 Mar 24;17(1):4360. doi: 10.1038/s41467-026-71009-7.
Mu Yang # 1 2,  Rulian Zhao # 3,  Li Peng # 1,  Liting Lv # 1,  Lanyao Yang 1,  Yunqi He 1,  Xu Ha 1,  Huijuan Xu 1,  Xiang Zhang 4,  Peiquan Zhao 4,  Shujin Li 5 6,  Zhenglin Yang 7 8 9
Affiliations

Affiliations

  • 1 Genetic Diseases Key Laboratory of Sichuan Province, Department of Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, PR China.
  • 2 Sichuan-Chongqing Joint Key Laboratory of Pathology and Laboratory Medicine, Jinfeng Laboratory, Chongqing, PR China.
  • 3 Department of Ophthalmology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, PR China.
  • 4 Department of Ophthalmology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
  • 5 Genetic Diseases Key Laboratory of Sichuan Province, Department of Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, PR China. [email protected].
  • 6 Sichuan-Chongqing Joint Key Laboratory of Pathology and Laboratory Medicine, Jinfeng Laboratory, Chongqing, PR China. [email protected].
  • 7 Genetic Diseases Key Laboratory of Sichuan Province, Department of Medical Genetics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, PR China. [email protected].
  • 8 Sichuan-Chongqing Joint Key Laboratory of Pathology and Laboratory Medicine, Jinfeng Laboratory, Chongqing, PR China. [email protected].
  • 9 Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, PR China. [email protected].
  • # Contributed equally.
PMID: 41872221 DOI: 10.1038/s41467-026-71009-7
Abstract

Familial exudative vitreoretinopathy is a hereditary disorder predominantly affecting infants and young children, often leading to severe vision loss. Approximately 40% of patients carry mutations in Norrin/β-catenin pathway genes. Nevertheless, the downstream pathogenic mechanisms remain unclear. Here, by using bulk RNA Sequencing and single-cell RNA Sequencing analyses, we identify KIF11 as a key downstream effector in retinal endothelial cells. Lentivirus-mediated KIF11 overexpression partially restores vascular defects in endothelial cell-specific Ctnnb1 knockout mice. Functional and multi-omics studies reveal that β-catenin/KIF11 deficiency induces autophagy-accompanied Ferroptosis. Mechanistically, KIF11 binds PRDX1, and the disrupted β-catenin/KIF11 axis releases the competitive restraint of KIF11 on Src-mediated PRDX1 phosphorylation, triggering subsequent liquid-liquid phase separation. Treatment with the Ferroptosis inhibitor ferrostatin-1 or lentiviral overexpression of non-phosphorylatable PRDX1 partially rescues vascular defects in familial exudative vitreoretinopathy-associated mice. Overall, we elucidate a β-catenin/KIF11/PRDX1 axis-dependent Ferroptosis mechanism in familial exudative vitreoretinopathy, highlighting ferroptosis-targeting and antioxidant strategies as potential therapies.

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