Epigenetic encoding of metabolic memory in diabetic retinopathy: From molecular imprinting to neurovascular network...

Diabetic retinopathy (DR) is increasingly recognized not merely as a microvascular complication, but as a chronic neurodegenerative disorder of the central nervous system characterized by progressive neurovascular unit (NVU) dysregulation. In many individuals, DR continues to progress despite subsequent glycaemic normalization, a phenomenon known as metabolic memory. Emerging evidence indicates that transient hyperglycaemic stress is converted into durable transcriptional programs through epigenetic encoding mechanisms. In this Review, we propose a hierarchical framework in which early metabolic insults are written into chromatin via DNA methylation, histone modifications, and noncoding RNA networks. Crucially, these epigenetic storage systems do not act in isolation; they systematically disrupt the intricate intercellular crosstalk within the NVU. Epigenetic locking of microglia into pro-inflammatory phenotypes, coupled with Müller cell gliosis and the suppression of neural plasticity, drives sustained pathological shifts that transform localized cellular stress into a tissue-wide network collapse. Furthermore, we critically evaluate the potential of extracellular vesicle-mediated communication in amplifying this memory across the NVU. By targeting the fundamental epigenetic drivers of glial reactivity and neurodegeneration across the integrated NVU, this Review highlights innovative strategies, such as programmable epigenetic editing (CRISPR/dCas9), to reset homeostasis and offers a transformative paradigm for early intervention in DR.