Homocysteine and mitophagy in diabetic retinopathy: unraveling the underlying molecular crosstalk

Diabetic retinopathy (DR), the leading cause of blindness among microvascular complications of diabetes, remains poorly understood regarding its pathogenesis, with effective clinical interventions remaining limited. Emerging evidence indicates that hyperhomocysteinemia (HHcy) and mitochondrial autophagy dysfunction act synergistically as key pathogenic drivers in DR progression, where their interactive cascade serves as a central mechanism disrupting retinal homeostasis.

This review systematically examines the complex mechanisms through which HHcy induces oxidative stress, inflammation, and endothelial dysfunction contributing to retinal injury, while elucidating the stage-specific regulatory dynamics of mitochondrial autophagy during DR pathogenesis.

We specifically investigate the molecular mechanism by which HHcy triggers mitochondrial autophagy dysfunction through oxidative stress-mediated regulation of the AMPK/mTOR signaling axis, thereby establishing a pathogenic positive feedback loop that accelerates DR progression.

Given the current lack of direct causal evidence, absence of retina-specific in vivo models, and incomplete understanding of their dynamic interactions, comprehensive analysis of core molecular nodes within the "HHcy-mitochondrial autophagy" regulatory axis is expected to refine the theoretical framework of DR pathogenesis while providing experimental foundations for developing targeted therapeutic strategies against DR-induced retinal damage.