Stage-dependent signaling networks and therapeutic strategies in diabetic retinopathy: from neurovascular dysfunction to angiogenesis and fibrosis.

Diabetic retinopathy (DR) is a consequence of multiple metabolic, neuronal, inflammatory, vascular and fibrotic changes, not a single cause. Early hyperglycaemia, oxidative stress, lipid disturbance, and mitochondrial dysfunction weaken the retinal neurovascular unit before clinically apparent vascular changes develop. With the accumulation of damage, nuclear factor kappa B, high-mobility group box 1, Toll-like receptor 4, receptor for advanced glycation end products, cyclic GMP-AMP synthase-stimulator of interferon genes, and the NOD-like receptor protein 3 inflammasome enhance inflammation, leukostasis and blood-retinal barrier dysfunction. Capillary loss then promotes hypoxia-inducible factor 1 alpha and vascular endothelial growth factor signalling, and angiopoietin-2, Wnt/beta-catenin, phosphoinositide 3-kinase/protein kinase B, semaphorin 4D, and endothelial metabolic reprogramming sustain leakage and neovascularisation. In advanced disease, Transforming Growth Factor Beta, Yes-associated Protein/transcriptional coactivator with PDZ-binding motif and related pathways drive extracellular matrix deposition, fibrovascular membrane formation and traction. Organise the mechanisms in this review according to disease stage and retinal cell type, and highlight pathway crosstalk, feedback loops, and altered biological functions during progression. Distinguish between clinical data and non-clinical studies, and conduct studies at all stages. Systemic metabolic control and fenofibrate have shown the most promise for early-stage disease, and anti-vascular endothelial growth factor therapy is still used in severe vascular complications. Anti-inflammatory, neuroprotective, anti-fibrotic, gene-based and multi-target approaches are promising but still have limitations in delivery, safety, model-to-human translation and weak biomarker validation. Improve the classification of molecules and find clinically significant early endpoints for targeted therapy.