线粒体自噬与糖尿病视网膜病变的研究进展

Research Advances in Mitophagy and Diabetic Retinopathy

摘要: 糖尿病视网膜病变(DR)是糖尿病最常见的微血管并发症，其病理机制涉及高血糖诱导的氧化应激、慢性炎症、VEGF异常活化及神经血管单元损伤。线粒体自噬作为选择性清除受损线粒体的关键机制，在DR中发挥双重作用：早期适度激活可清除功能障碍的线粒体，保护视网膜细胞；而在持续高糖状态下，其功能常发生失调，导致受损线粒体累积，加剧氧化损伤与炎症反应，推动DR进展。当前主流抗VEGF疗法存在应答率不一、治疗负担重及无法逆转“代谢记忆”等局限。因此，靶向调控线粒体自噬已成为新兴治疗策略。研究显示，小分子调节剂、基因疗法及干细胞来源胞外囊泡递送系统等在临床前模型中能改善线粒体功能、减轻DR损伤。然而，其临床转化仍面临细胞特异性调控、递送效率及模型转化等多重挑战，未来需进一步阐明其调控网络，以推动DR治疗的发展。

Abstract: Diabetic retinopathy (DR) is the most common microvascular complication of diabetes, with its pathological mechanism involving hyperglycemia-induced oxidative stress, chronic inflammation, abnormal activation of VEGF, and neurovascular unit injury. As a key mechanism for selectively clearing damaged mitochondria, mitophagy plays a dual role in DR: moderate activation in the early stage can remove dysfunctional mitochondria and protect retinal cells; however, under persistent hyperglycemia, its function often becomes dysregulated, leading to the accumulation of damaged mitochondria, exacerbating oxidative damage and inflammatory responses, and driving the progression of DR. Current mainstream anti-VEGF therapies have limitations such as inconsistent response rates, high treatment burden, and inability to reverse “metabolic memory”. Therefore, targeted regulation of mitophagy has emerged as a novel therapeutic strategy. Studies have shown that small-molecule modulators, gene therapies, and stem cell-derived extracellular vesicle delivery systems can improve mitochondrial function and alleviate DR damage in preclinical models. However, their clinical translation still faces multiple challenges, including cell-specific regulation, delivery efficiency, and model translatability. Future research needs to further clarify the regulatory network of mitophagy to advance the development of DR treatments.