From retina to triple-monitoring: One-carbon metabolism in diabetic retinopathy

Diabetic retinopathy (DR) is a microvascular complication of diabetes characterized by blood-retinal barrier (BRB) disruption and progressive endothelial dysfunction. Disturbances in one-carbon metabolism, particularly hyperhomocysteinemia (HHcy), have been implicated as biologically plausible modifiers of retinal endothelial vulnerability.

To synthesize mechanistic, preclinical, and clinical evidence linking HHcy and one-carbon metabolism to BRB dysfunction in DR, and to explore translational implications for endothelial risk assessment.

Narrative review of experimental, observational, and translational studies examining homocysteine metabolism, endothelial regulation, BRB integrity, and diabetes-induced metabolic perturbations. Evidence was prioritized based on mechanistic relevance, in vitro and in vivo models, and human correlates.

Elevated homocysteine promotes oxidative stress, tight junction destabilization, N-methyl-d-aspartate receptor activation, mitochondrial dysfunction, and impaired mitophagy in retinal endothelial cells. Diabetes amplifies these pathways, lowering the threshold for VEGF-mediated BRB breakdown. Observational studies associate HHcy with DR severity, but causality remains unproven. Cardiovascular trials demonstrate plasma homocysteine lowering without consistent macrovascular benefit, suggesting HHcy functions primarily as a biomarker or modifier. Emerging data indicate potential intersections with innate immune signaling and ferroptotic vulnerability, offering mechanistic hypotheses for translational research. Integrative frameworks considering glycemic control, one-carbon metabolic status, and endothelial signaling may inform future early-intervention strategies, though clinical validation is pending.

HHcy represents a mechanistic modifier of retinal endothelial stress in DR rather than a validated therapeutic target. Anti-VEGF therapy and glycemic optimization remain the only proven interventions. Further studies clarifying intracellular one-carbon metabolism and BRB integrity may refine risk stratification and identify early-intervention opportunities.