Diabetic retinal neurovascular unit injury: mechanisms, imaging evaluation, and integrated therapeutic strategies

Abstract

Diabetic retinopathy (DR) has long been regarded as an isolated retinal microvascular disease. Histopathological, molecular, imaging, and multi-omics evidence now supports disruption of retinal neurovascular unit (NVU) homeostasis as a central mechanism of DR, in which neuronal degeneration, reactive gliosis, and microvascular damage reinforce one another. This narrative review summarizes the anatomy and physiology of the NVU, its temporal evolution in DR, the molecular pathways of neurovascular crosstalk, quantitative imaging assessment, and integrated therapeutic strategies, and indicates where the evidence remains uncertain. PubMed, Embase, and Web of Science were searched from inception to July 2026 for reports on the retinal NVU in diabetes, and reference lists of retrieved articles were screened. Because this is a narrative rather than a systematic review, records were screened by the authors without a formal risk-of-bias assessment or quantitative synthesis. English-language reports addressing retinal NVU structure, diabetes-related injury mechanisms, imaging quantification, or NVU-directed interventions were eligible, and priority was given to human histopathological studies, prospective imaging cohorts, and translational intervention studies. Eighty-two references were included. Neurodegeneration is the earliest readily detectable change of NVU dysfunction in most cohorts, whereas microvascular injury amplifies retinal damage. Combined optical coherence tomography (OCT), OCT angiography (OCTA), and electroretinography (ERG) allow stage-specific quantification, and ganglion cell–inner plexiform layer (GCIPL) and deep capillary plexus vessel density (DVD) are among the most consistently reported early markers, although this evidence varies. Polyol pathway activation, AGE–RAGE and protein kinase C signaling, oxidative stress, HIF-1 α /vascular endothelial growth factor (VEGF) signaling, microglial STING and inflammasome activation, and non-coding RNA dysregulation jointly mediate bidirectional neurovascular injury. Vascular-targeted monotherapy cannot halt inner retinal neuronal loss, whereas multi-target strategies remain largely preclinical or at an early trial stage. In our interpretation, early neurodegeneration is the most readily detectable biomarker, microcirculatory damage acts as a disease amplifier, and complete NVU disintegration is the terminal common pathway. This framework is proposed to support ultra-early risk stratification and synergistic multi-target intervention, and is offered as one interpretation of a still-evolving evidence base rather than an established consensus.