Retinal pigment epithelium in diabetic retinopathy: Interplay of inflammation, oxidative stress, apoptosis, and ncRNA alterations.

Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults and results from chronic hyperglycemia-induced damage to retinal cells. The retinal pigment epithelium (RPE), located between the neuroretina and choroid, is a critical regulator of retinal homeostasis and an important target of hyperglycemic injury. The aim of this review is to systematically summarize and critically evaluate the molecular mechanisms by which prolonged hyperglycemia disrupts RPE function, with emphasis on four interconnected pathological processes: inflammation, oxidative stress, apoptosis, and non-coding RNA (ncRNA) dysregulation. Hyperglycemia promotes the production of pro-inflammatory cytokines and reactive oxygen species, activates signaling pathways that compromise barrier integrity, and induces apoptotic cell loss. Concurrent alterations in microRNA and long ncRNA expression further impair cellular resilience, metabolic homeostasis, and angiogenic balance. We also review experimental evidence supporting the use of natural and synthetic compounds that target these pathways and may preserve RPE function under hyperglycemic conditions. In addition, we integrate a bioinformatic analysis of DR associated protein-protein interaction networks to identify central regulatory nodes and highlight potential molecular targets for future mechanistic and translational studies.