Liu Danjuan, Zheng Zheng, Chen Zhicheng, Guo Rongjie, Weng Junting, Huang Shanjiao, Weng Shuoyun
Department of Critical Care Medicine, the Affiliated Hospital of Putian University, Putian, 351100, China.
School of Ophthalmology & Optometry, Wenzhou Medical University, No. 270 Xueyuan Road, Lucheng District, Wenzhou City, Zhejiang Province, China.
Int Ophthalmol. 2025 Jul 21;45(1):302. doi: 10.1007/s10792-025-03681-5.
Diabetic retinopathy (DR), traditionally considered a microvascular complication, is now increasingly recognized as a neurodegenerative and neuroinflammatory disorder. Among retinal glial cells, Müller cells are particularly susceptible to hyperglycemia-induced stress, playing a pivotal role in the progression of DR.
This review aims to systematically summarize the mechanisms by which high glucose induces ferroptosis in Müller cells and to explore the implications of ferroptotic damage for retinal neuroinflammation and blood-retinal barrier dysfunction in DR.
A comprehensive literature review was conducted focusing on recent experimental and translational studies related to ferroptosis pathways in diabetic retinal environments, particularly involving Müller cell pathology.
Hyperglycemia promotes Müller cell ferroptosis via three major axes: 1. Iron metabolism dysregulation, including TfR1/DMT1 upregulation and autophagic degradation of ferritin (ferritinophagy); 2. Enhanced lipid peroxidation, driven by ACSL4 and lipoxygenase (LOX) activity; 3. Antioxidant system impairment, notably via suppression of the system Xc⁻/GPX4 axis. Ferroptosis in Müller cells contributes to neuroinflammation through the release of damage-associated molecular patterns (DAMPs), activation of retinal microglia, and disruption of the blood-retinal barrier.
Ferroptosis is a critical and previously underappreciated mechanism linking metabolic stress to neuroinflammation in DR. Targeting ferroptosis-via iron chelation, GPX4 restoration, or activation of the Nrf2 pathway-represents a promising therapeutic strategy to mitigate retinal neurodegeneration in diabetic patients.
糖尿病视网膜病变（DR）传统上被认为是一种微血管并发症，现在越来越被视为一种神经退行性和神经炎症性疾病。在视网膜神经胶质细胞中，穆勒细胞对高血糖诱导的应激特别敏感，在DR的进展中起关键作用。
本综述旨在系统总结高糖诱导穆勒细胞铁死亡的机制，并探讨铁死亡损伤对DR中视网膜神经炎症和血视网膜屏障功能障碍的影响。
进行了一项全面的文献综述，重点关注与糖尿病视网膜环境中铁死亡途径相关的最新实验和转化研究，特别是涉及穆勒细胞病理学的研究。
高血糖通过三个主要轴促进穆勒细胞铁死亡：1. 铁代谢失调，包括转铁蛋白受体1（TfR1）/二价金属离子转运体1（DMT1）上调和铁蛋白的自噬降解（铁蛋白自噬）；2. 由长链脂酰辅酶A合成酶4（ACSL4）和脂氧合酶（LOX）活性驱动的脂质过氧化增强；3. 抗氧化系统受损，特别是通过抑制系统Xc⁻/谷胱甘肽过氧化物酶4（GPX4）轴。穆勒细胞中的铁死亡通过释放损伤相关分子模式（DAMPs）、激活视网膜小胶质细胞和破坏血视网膜屏障导致神经炎症。
铁死亡是DR中连接代谢应激与神经炎症的一种关键且此前未得到充分认识的机制。通过铁螯合、恢复GPX4或激活核因子E2相关因子2（Nrf2）途径靶向铁死亡，是减轻糖尿病患者视网膜神经退行性变的一种有前景的治疗策略。
