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KIF11 prevents retinal endothelial ferroptosis in familial exudative vitreoretinopathy by inhibiting
Mu Yang1,2, Rulian Zhao3, Li Peng1
1Genetic 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.
Insights
Familial exudative vitreoretinopathy involves KIF11, a key protein in retinal cells. Its deficiency triggers ferroptosis, a cell death process, offering new therapeutic targets for vision loss.
Area of Science:
- Ophthalmology
- Genetics
- Cell Biology
Background:
- Familial exudative vitreoretinopathy (FEVR) is an inherited condition causing severe vision loss, particularly in children.
- Mutations in Norrin/β-catenin pathway genes are found in ~40% of FEVR patients, but downstream mechanisms are unknown.
Purpose of the Study:
- To identify key downstream effectors in retinal endothelial cells affected by FEVR.
- To elucidate the pathogenic mechanisms linking β-catenin deficiency to vascular defects and vision loss in FEVR.
Main Methods:
- Bulk and single-cell RNA sequencing analyses to identify KIF11 as a key effector.
- Lentivirus-mediated gene manipulation in endothelial cell-specific Ctnnb1 knockout mice.
- Functional assays and multi-omics studies to investigate molecular pathways.
Main Results:
- KIF11 was identified as a critical downstream effector in retinal endothelial cells.
- β-catenin/KIF11 deficiency induces autophagy-accompanied ferroptosis.
- The β-catenin/KIF11 axis regulates PRDX1 phosphorylation and liquid-liquid phase separation, impacting vascular integrity.
Conclusions:
- A novel β-catenin/KIF11/PRDX1 axis-dependent ferroptosis mechanism underlies FEVR pathogenesis.
- Targeting ferroptosis and employing antioxidant strategies show potential for FEVR therapy.
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.
