Pharmacological Modulation of the Nrf2–Keap1 Pathway in Diabetes: Mechanisms, Therapeutic Advances, and Future Directions

Diabetes mellitus remains a major global challenge driven by oxidative stress, inflammation, and metabolic imbalance. The nuclear factor erythroid 2–related factor 2 (Nrf2)–Kelch-like ECH-associated protein 1 (Keap1) pathway acts as a pivotal intracellular Défense axis against redox and inflammatory insults. This review comprehensively explores the pharmacological modulation of the Nrf2–Keap1 system in diabetic complications, including nephropathy, retinopathy, neuropathy, and cardiomyopathy. Natural compounds such as sulforaphane, curcumin, and resveratrol, alongside synthetic activators like bardoxolone methyl and dimethyl fumarate, demonstrate multi-organ protection through the restoration of antioxidant, mitochondrial, and anti-fibrotic functions. However, translation to clinical success remains constrained by poor bioavailability, tissue-selectivity issues, and safety concerns. Advanced drug-delivery platforms, such as redox-responsive nanocarriers and prodrug formulations, offer promising precision in targeting oxidative microenvironments. Future therapeutic paradigms should integrate controlled Nrf2 activation with metabolic modulators, including SGLT2 inhibitors and GLP-1 receptor agonists, to achieve synergistic efficacy without exceeding toxicity thresholds. Ultimately, the convergence of pharmacogenomic profiling, biomarker discovery, and nanotechnological innovation is expected to transform Nrf2-based interventions from experimental insights into clinically viable therapies for diabetes management.