KIF11 prevents retinal endothelial ferroptosis in familial exudative vitreoretinopathy by inhibiting phosphorylation-driven PRDX1 phase separation PMID: 41872221

ADC Targets in Oncology

2026-04-10

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

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.

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.