Neurovascular dysfunction in diabetic retinopathy: mechanisms and therapeutic perspectives

Diabetic retinopathy (DR) involves dysfunction of the retinal neurovascular unit (NVU) in addition to clinically detectable microvascular lesions. This narrative review critically examines how metabolic and organelle stress, neuroglial inflammation, and blood–retinal barrier dysfunction contribute to impaired retinal homeostasis. We propose an evidence-to-decision framework that distinguishes candidate initiating mechanisms, disease amplifiers, persistence programs, and potential treatment-escape pathways according to the strength of causal evidence and clinical relevance. Findings from human studies, experimental models, and clinical trials are evaluated separately to avoid conflating molecular associations with established mechanisms of disease progression. Particular attention is given to the distinction between clinical metabolic memory and experimentally demonstrated molecular persistence, as well as between alternative angiogenic signaling and clinically validated resistance to vascular endothelial growth factor inhibition. Emerging imaging, electrophysiological, and molecular biomarkers may help characterize neurovascular heterogeneity, but their prognostic and predictive value remains insufficiently established. We identify key experimental and clinical studies needed to validate mechanistic hypotheses, clarify their relationship to functional outcomes, and assess their therapeutic relevance. This synthesis provides a framework for prioritizing testable mechanisms while emphasizing that mechanism-guided patient stratification and treatment selection require prospective clinical validation.