Fuente: PubMed "nature biotechnology" Stem Cell Rev Rep. 2026 Aug 20. doi: 10.1007/s12015-026-11213-6. Online ahead of print.ABSTRACTDiabetic retinopathy (DR) is a leading cause of vision loss and is now increasingly understood as a neurovascular disease rather than a purely microvascular complication of diabetes. The retinal neurovascular unit (NVU), composed of neurons, Müller cells, microglia, astrocytes, endothelial cells, pericytes, and extracellular matrix components, integrates neural activity, vascular perfusion, barrier integrity, and inflammatory control. In diabetes, NVU injury develops through a hierarchical and self-amplifying process. Upstream metabolic and systemic triggers, including hyperglycemia, advanced glycation end products (AGEs), homocysteine and lipid imbalance, and NADPH oxidase-derived reactive oxygen species, initiate cellular stress. These triggers converge on mitochondrial dysfunction, impaired autophagy and mitophagy, endoplasmic reticulum stress, and mitochondrial DNA release, which subsequently activate innate immune pathways. Neuroinflammatory amplification driven by microglial activation, Müller cell gliosis, NLRP3 inflammasome signaling, pyroptosis, and cytokine feedback further links neuronal and vascular injury. The final common pathway is integrated NVU breakdown, characterized by retinal neurodegeneration, pericyte loss, endothelial dysfunction, blood-retinal barrier disruption, vascular leakage, and VEGF-driven neovascularization. Regulatory RNA networks, including lncRNAs, miRNAs, circRNAs, piRNAs, and tRNA-derived fragments, act as cross-cutting epigenetic regulators of these processes. This review integrates current evidence within an NVU-centered systems biology framework and aligns therapeutic strategies with the disease hierarchy, distinguishing established clinical treatments from preclinical and emerging interventions.PMID:42622757 | DOI:10.1007/s12015-026-11213-6