Diabetic retinopathy as a metabolic-inflammatory complication of diabetes: Endocrine crosstalk, molecular mechanisms, and translational therapeutic strategies

Diabetic retinopathy (DR) is a leading cause of vision loss and a major microvascular complication of diabetes mellitus, increasingly recognized as a systemic metabolic-endocrine disorder rather than an isolated ocular disease. Chronic hyperglycemia, insulin resistance, lipid dysregulation, and metabolic memory converge to induce oxidative stress, mitochondrial dysfunction, chronic inflammation, and pathological angiogenesis within retinal tissues. These interconnected mechanisms promote neurovascular degeneration and progressive retinal dysfunction. This review provides an updated and integrative overview of the molecular and cellular mechanisms underlying DR, with emphasis on key signaling pathways including NF-κB activation, NLRP3 inflammasome signaling, VEGF-mediated angiogenesis, and mitochondrial impairment. Particular attention is given to the roles of insulin resistance, advanced glycation end products (AGEs), endocrine imbalance, and persistent metabolic injury in initiating and sustaining retinal damage. Current and emerging therapeutic strategies are critically discussed, including anti-VEGF agents, corticosteroids, gene therapy, sustained drug delivery systems, and metabolically targeted interventions. In addition, translational tools such as biomarker discovery, multi-omics profiling, and artificial intelligence are highlighted as promising approaches for patient stratification and precision medicine. Overall, this review positions DR as a prototypical metabolic inflammatory complication of diabetes and underscores the importance of integrating systemic metabolic control with retinal targeted therapies to achieve durable clinical outcomes and advance personalized disease management.