KIF11通过抑制磷酸化驱动的PRDX1相分离来预防家族性渗出性玻璃体视网膜病变中的视网膜内皮细胞铁下垂
KIF11 prevents retinal endothelial ferroptosis in familial exudative vitreoretinopathy by inhibiting phosphorylation-driven PRDX1 phase separation.
摘要(中文译文)
家族性渗出性玻璃体视网膜病变是一种主要影响婴幼儿的遗传性疾病，常导致严重视力丧失。约40%的患者携带Norrin/β-catenin通路基因突变。然而，其下游致病机制仍不清楚。本研究通过批量RNA测序和单细胞RNA测序分析，鉴定出KIF11是视网膜内皮细胞中的关键下游效应分子。慢病毒介导的KIF11过表达可部分恢复内皮细胞特异性Ctnnb1敲除小鼠的血管缺陷。功能学和多组学研究揭示，β-catenin/KIF11缺失可诱导伴随自噬的铁死亡。在机制上，KIF11与PRDX1结合，而受损的β-catenin/KIF11轴解除了KIF11对Src介导的PRDX1磷酸化的竞争性抑制，从而触发随后的液-液相分离。使用铁死亡抑制剂ferrostatin-1或慢病毒过表达不可磷酸化的PRDX1可部分挽救家族性渗出性玻璃体视网膜病变相关小鼠的血管缺陷。总体而言，我们阐明了家族性渗出性玻璃体视网膜病变中依赖β-catenin/KIF11/PRDX1轴的铁死亡机制，突出靶向铁死亡和抗氧化策略作为潜在治疗方法。
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.
如何引用
AMA
Mu Yang, Rulian Zhao, Li Peng, Liting Lv, Lanyao Yang, Yunqi He, et al. KIF11 prevents retinal endothelial ferroptosis in familial exudative vitreoretinopathy by inhibiting phosphorylation-driven PRDX1 phase separation.. Nature communications. 2026; doi:10.1038/s41467-026-71009-7.
APA
Mu Yang, Rulian Zhao, Li Peng, Liting Lv, Lanyao Yang, Yunqi He, et al (2026). KIF11 prevents retinal endothelial ferroptosis in familial exudative vitreoretinopathy by inhibiting phosphorylation-driven PRDX1 phase separation.. Nature communications. https://doi.org/10.1038/s41467-026-71009-7
GB/T 7714
Mu Yang, Rulian Zhao, Li Peng, Liting Lv, Lanyao Yang, Yunqi He, et al. KIF11 prevents retinal endothelial ferroptosis in familial exudative vitreoretinopathy by inhibiting phosphorylation-driven PRDX1 phase separation.[J]. Nature communications, 2026 doi:10.1038/s41467-026-71009-7.
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