Neurodegeneration as an early driver and therapeutic target in diabetic retinopathy

Diabetic retinopathy (DR) is conventionally recognized as a microvascular complication of diabetes mellitus. Nevertheless, accumulating evidence confirms that early retinal neurodegeneration develops in the course of diabetes and drives early visual impairment. Multiple studies have verified that abnormal retinal neural responses frequently emerge before identifiable microvascular lesions. This review therefore systematically summarizes existing evidence confirming retinal neurodegeneration as a core, early pathological event in diabetic retinal disease (DRD), elaborates the cellular and metabolic mechanisms of neurodegeneration inside the retinal neurovascular unit (NVU), and assesses novel neuroprotective therapeutic modalities. Retinal neurodegeneration manifests prior to clinically apparent microvascular complications. NVU dysfunction, triggered by neuroinflammation, oxidative stress, advanced glycation end products (AGEs), excitotoxicity and mitochondrial dysfunction, serves as the pivotal pathway mediating neuronal injury. Notably, current vasculotropic therapies fail to effectively block early neuronal dysfunction. By comparison, neuroprotective interventions targeting oxidative stress, inflammatory cascades, glial dysfunction, deficient neurotrophic supply and mitochondrial damage exhibit promising effects on maintaining retinal neuronal architecture and function. In conclusion, retinal neurodegeneration constitutes a core pathological cascade of DR. Incorporating neuroprotective regimens into established treatment systems facilitates earlier intervention, optimizes visual function prognosis, and ultimately transforms the clinical management paradigm of DRD toward retinal neural protection.