Guo Dongling, Du Yu, Liu Xin, Li Dan, Wei Ling, Zhu Xiangjia
Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.
Key Laboratory of Myopia and Related Eye Diseases, NHC; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China.
Cell Death Dis. 2025 Feb 3;16(1):64. doi: 10.1038/s41419-025-07384-8.
Highly myopic cataract (HMC) is a leading cause of blindness among the working-age individuals, with its pathogenesis poorly understood. This study aimed to elucidate the role of ferroptosis in HMC development as well as the underlying mechanisms. In HMC lens epithelia, levels of Fe and lipid peroxidation were found elevated, with increased vulnerability towards ferroptosis as revealed by transmission electron microscopy. Mechanistically, RNA sequencing of HMC lens epithelial samples identified up-regulated expression of discoidin domain receptor tyrosine kinase 2 (DDR2) as a key factor, which could enhance ferroptosis sensitivity via the Src-Hippo pathway. Specifically, DDR2 interacted with Src kinase, leading to the nuclear translocation of homologous transcriptional regulators (yes-associated protein 1 [YAP1] and WW domain containing transcription regulator 1 [WWTR1]) of the Hippo pathway, which altered the expression level of ferroptosis-related genes. Notably, highly myopic eyes of mice exhibited higher sensitivity to RSL3, a ferroptosis inducer, manifested as more severe nuclear lens opacities both in vitro and in vivo compared with the contralateral control eyes, which could be alleviated by inhibitors of either ferroptosis or DDR2. Altogether, these findings highlighted the role of DDR2 in mediating ferroptosis in HMC formation, providing a novel insight for therapeutic interventions.
高度近视性白内障（HMC）是导致工作年龄人群失明的主要原因之一，其发病机制尚不清楚。本研究旨在阐明铁死亡在HMC发展中的作用及其潜在机制。在HMC晶状体上皮细胞中，发现铁和脂质过氧化水平升高，透射电子显微镜显示对铁死亡的易感性增加。机制上，对HMC晶状体上皮样本进行RNA测序，确定盘状结构域受体酪氨酸激酶2（DDR2）表达上调是一个关键因素，它可通过Src-Hippo途径增强铁死亡敏感性。具体而言，DDR2与Src激酶相互作用，导致Hippo途径的同源转录调节因子（Yes相关蛋白1 [YAP1]和含WW结构域的转录调节因子1 [WWTR1]）发生核转位，从而改变铁死亡相关基因的表达水平。值得注意的是，与对侧对照眼相比，小鼠高度近视眼对铁死亡诱导剂RSL3表现出更高的敏感性，在体外和体内均表现为更严重的晶状体核混浊，而铁死亡抑制剂或DDR2抑制剂均可缓解这种情况。总之，这些发现突出了DDR2在介导HMC形成过程中铁死亡中的作用，为治疗干预提供了新的见解。
