The protective role of vitamin C in diabetic retinopathy and TPT1 as a potential therapeutic target

BACKGROUND: Diabetic retinopathy (DR), the primary driver of preventable vision impairment in the global working-age demographic, arises from chronic hyperglycaemia and manifests as non-proliferative or proliferative retinopathy with or without diabetic macular oedema. Inflammation and macrophage-derived cytokines drive progression, and proteomics can identify proteins that may be associated with DR. Vitamin C has been implicated in diabetic complications, yet its causal impact on DR remains unclear. METHODS: We performed quantitative proteomics and bioinformatics analyses of peripheral-blood macrophages from patients with proliferative DR (PDR), non-PDR, diabetes without retinopathy and non-diabetic controls. In a series of experiments, we used THP-1 cells exposed to sustained hyperglycemia and retinal lysates from streptozotocin (STZ)-induced mice to quantify TPT1 expression and to investigate its role in modulating autophagy-related mediators and cellular redox homeostasis. Causal inference between circulating vitamin C and DR risk was tested by two-sample Mendelian randomization (MR). RESULTS: Quantitative profiling revealed 265 proteins whose abundance differed significantly between PDR and controls; 145 were up-regulated and 120 down-regulated, with TPT1 emerging as a central hub within the macrophage interactome. TPT1 expression was markedly reduced under hyperglycemic conditions, which was accompanied by impaired autophagic activity and increased reactive oxygen species production. MR analysis revealed that vitamin C levels were negatively correlated with the risk of DR (OR = 0.09, 95% CI: 0.01-0.57, P = 0.01). CONCLUSIONS: Deficiency of TPT1 links impaired macrophage autophagy to the progression of diabetic retinopathy, while vitamin C, which restores TPT1 expression, represents a promising therapeutic strategy.