Neddylation as a molecular integrator of metabolic dysfunction and endothelial dysfunction in type 2 diabetes

Abstract Type 2 diabetes mellitus (T2D) is a major global health challenge associated with a high burden of cardiovascular and microvascular complications. Endothelial dysfunction is a hallmark of T2D and represents a critical link between metabolic abnormalities and vascular disease. Chronic hyperglycemia, insulin resistance, obesity-associated inflammation, oxidative stress, and mitochondrial dysfunction disrupt endothelial homeostasis, resulting in impaired nitric oxide bioavailability, vascular inflammation, endothelial senescence, barrier dysfunction, and defective vascular repair. However, the molecular mechanisms integrating metabolic stress with endothelial injury in T2D remain incompletely understood. Neddylation is a reversible ubiquitin-like post-translational modification mediated by neural precursor cell expressed, developmentally downregulated 8 (NEDD8). Through activation of Cullin-RING E3 ubiquitin ligases and modification of non-cullin substrates, neddylation regulates protein turnover, signal transduction, metabolism, inflammation, oxidative stress responses, and mitochondrial homeostasis. Emerging evidence suggests that dysregulated neddylation contributes to several metabolic abnormalities implicated in endothelial dysfunction, including insulin resistance, obesity-associated metabolic dysfunction, oxidative stress, and mitochondrial dysfunction. In diabetic retinopathy, excessive cullin neddylation promotes degradation of protective factors such as nuclear factor erythroid 2-related factor 2 (NRF2) and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), thereby enhancing oxidative stress, inflammation, vascular leakage, and pathological angiogenesis. Conversely, physiological neddylation appears necessary for endothelial homeostasis through regulation of endothelial barrier integrity, angiogenesis, and stabilization of vascular endothelial growth factor receptor 2 (VEGFR2). Although direct evidence remains largely limited to retinal endothelial cells and diabetic retinopathy models, current findings support the hypothesis that dysregulated neddylation may act as an important molecular link between metabolic dysfunction and endothelial injury in diabetes. Pharmacological modulation of the neddylation pathway, including inhibition of the NEDD8-activating enzyme with MLN4924 (pevonedistat), improves metabolic homeostasis, suppresses inflammatory signaling, enhances antioxidant defenses, and attenuates vascular injury in preclinical studies. In this review, we summarize current advances in neddylation biology, discuss emerging evidence linking dysregulated neddylation to diabetes-associated endothelial dysfunction, highlight critical knowledge gaps, and evaluate the opportunities and challenges of targeting the neddylation pathway for the prevention and treatment of diabetic vascular complications.