Yuan Fang, Han Songyu, Li Yahong, Li Sanming, Li Dian, Tian Qingjun, Feng Ronghua, Shao Ying, Liang Xing, Wang Jingbo, Lei Hetian, Li Xiaorong, Duan Yajian
Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China; Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China; Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China.
Exp Eye Res. 2025 Apr;253:110299. doi: 10.1016/j.exer.2025.110299. Epub 2025 Feb 18.
Ferroptosis has been implicated in the development of diabetic retinopathy (DR). This study aimed to identify novel ferroptosis-related regulators involved in the pathophysiology of DR using an in vivo streptozotocin (STZ)-induced diabetic model in C57BL/6J mice and cultured primary human retinal vascular endothelial cells (HRECs). Transmission electron microscopy revealed mitochondrial morphological changes consistent with ferroptosis in vascular endothelial cells from STZ-treated mice. Western blot analysis showed increased levels of ferroptosis markers (4-HNE, p53, phosphorylated p53) along with decreased levels of glutathione (GSH), SLC7A11, and GPX4 in diabetic mice. In vitro experiments demonstrated that ferroptosis inhibitors, including pifithrin-α (a p53 inhibitor) and ferrostatin-1 (Fer-1), mitigated cellular damage and Fe accumulation in high-glucose-treated HRECs. These inhibitors also improved mitochondrial membrane potential and restored GSH levels. Bioinformatics analysis and dual-luciferase assays identified a p53 binding site within the miR-214-3p sequence. Overexpression of miR-214-3p in high-glucose-treated HRECs resulted in downregulation of p53 and upregulation of SLC7A11 and GPX4, thereby alleviating ferroptosis-induced injury. This study demonstrates that ferroptosis contributes to retinal damage at tissue, cellular, and molecular levels in DR. Specifically, p53, regulated by miR-214-3p, promotes ferroptosis through the SLC7A11/GPX4 pathway under high-glucose conditions. These findings suggest that the miR-214-3p/p53/SLC7A11/GPX4 axis could serve as a potential therapeutic target for managing ferroptosis and retinal damage in diabetic retinopathy.
铁死亡与糖尿病视网膜病变（DR）的发生发展有关。本研究旨在利用链脲佐菌素（STZ）诱导的C57BL/6J小鼠糖尿病体内模型和培养的原代人视网膜血管内皮细胞（HRECs），鉴定参与DR病理生理过程的新型铁死亡相关调节因子。透射电子显微镜显示，STZ处理小鼠的血管内皮细胞中线粒体形态变化与铁死亡一致。蛋白质印迹分析表明，糖尿病小鼠中铁死亡标志物（4-羟基壬烯醛、p53、磷酸化p53）水平升高，同时谷胱甘肽（GSH）、溶质载体家族7成员11（SLC7A11）和谷胱甘肽过氧化物酶4（GPX4）水平降低。体外实验表明，铁死亡抑制剂，包括pifithrin-α（一种p53抑制剂）和铁抑素-1（Fer-1），可减轻高糖处理的HRECs中的细胞损伤和铁积累。这些抑制剂还改善了线粒体膜电位并恢复了GSH水平。生物信息学分析和双荧光素酶测定确定了miR-214-3p序列内的一个p53结合位点。在高糖处理的HRECs中过表达miR-214-3p导致p53下调以及SLC7A11和GPX4上调，从而减轻铁死亡诱导的损伤。本研究表明，铁死亡在DR的组织、细胞和分子水平上导致视网膜损伤。具体而言，在高糖条件下，受miR-214-3p调控的p53通过SLC7A11/GPX4途径促进铁死亡。这些发现表明，miR-214-3p/p53/SLC7A11/GPX4轴可能成为治疗糖尿病视网膜病变中铁死亡和视网膜损伤的潜在治疗靶点。
