Homocysteine and diabetic retinopathy

Diabetic retinopathy (DR), a leading cause of blindness in working-age adults, is a complex neurovascular complication of diabetes mellitus. Beyond chronic hyperglycemia, hyperhomocysteinemia (HHcy) has emerged as a significant modulator of DR progression. This review delineates the multifaceted role of HHcy in disrupting the retinal neurovascular unit, detailing its pathogenic impact on endothelial cells, neurons (particularly retinal ganglion cells), glial cells, and the retinal pigment epithelium. The molecular mechanisms involve a synergistic interplay of oxidative stress, inflammation, endoplasmic reticulum stress, mitochondrial dysfunction, and epigenetic dysregulation, culminating in blood-retinal barrier breakdown, neurodegeneration, and pathological angiogenesis. While preclinical evidence robustly demonstrates a direct and synergistic effect of homocysteine with hyperglycemia in driving retinal injury, clinical associations remain contentious due to heterogeneity in study populations, confounding factors like renal function, and methodological variations. We critically evaluate this translational evidence and explore the therapeutic potential of targeting homocysteine metabolism through B vitamins, betaine, and other strategies. Despite promising preliminary data, the field requires well-designed randomized controlled trials, informed by lessons from cardiovascular research, to definitively establish HHcy as a modifiable risk factor and to validate the efficacy of precise, personalized interventions for DR.