Cellular Senescence in Diabetic Retinopathy: Molecular Mechanisms and Therapeutic Targeting

Background Diabetic retinopathy (DR) is the leading cause of vision loss in the working-age population, traditionally attributed to metabolic disorders and microvascular damage induced by chronic hyperglycemia. Emerging evidence indicates that cellular senescence acts as a critical upstream driver of DR, with senescent cells accumulating in the retina and secreting a senescence-associated secretory phenotype (SASP) that promotes chronic inflammation, pathological angiogenesis, and disruption of the blood-retinal barrier (BRB). Main text This review adopts a neurovascular unit (NVU) perspective to synthesize cell-type-specific senescence phenotypes in the diabetic retina, emphasizing that endothelial cell, pericyte, retinal pigment epithelium, microglial, and retinal ganglion cell senescence constitute an interconnected pathological network rather than isolated events. NVU-wide senescence establishes a self-reinforcing cycle: senescent endothelial and pericyte dysfunction drives vascular instability; retinal pigment epithelial cells (RPE) senescence compromises the outer BRB; and glial and retinal ganglion cell (RGC) senescence amplifies neuroinflammation and neurodegeneration. We dissect key molecular drivers—oxidative DNA damage, epigenetic reprogramming (miRNA/Sirtuins), mitophagy impairment, and SASP-mediated inflammatory feedforward—and critically evaluate emerging senotherapeutics (senolytics, senomorphics, and precision delivery platforms) within an evidence-graded framework. Conclusions Cellular senescence establishes a progressive senescence-inflammation vicious cycle in DR, affecting multiple interconnected cell types within the NVU and causing neurovascular dysfunction. Targeting cellular senescence through senescent cell clearance, SASP inhibition, mitochondrial homeostasis regulation, and epigenetic modulation offers promising new therapeutic directions. With the advancement of novel senotherapeutics and precision technologies, personalized early treatment and retinal repair for DR may become achievable in the future.