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

Authors

  • Amar Saxena Department of Pharmacy, Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, INDIA https://orcid.org/0009-0006-3593-6927
  • Shrestha Saxena Department of Arts, Lalit Kala Sansthan, Agra, Uttar Pradesh, INDIA
  • Yash Saxena Department of Pharmacy, Anand College of Pharmacy, Agra, Uttar Pradesh, INDIA
  • Ashita Jain Department of Pharmacy, Sharda School of Pharmacy, Agra, Uttar Pradesh, INDIA
  • Rama Chaudhary Faculty of Pharmacy, Agrawan Heritage University, Agra, Uttar Pradesh, INDIA
  • Pooja Bharti Faculty of Pharmacy, Agrawan Heritage University, Agra, Uttar Pradesh, INDIA
  • Shivdeep Mishra Department of Pharmacy, College of Pharmacy, Agra, Uttar Pradesh, INDIA
  • Chandrabhan Singh Department of Pharmacy, ABESIT College of Pharmacy, Ghaziabad, Uttar Pradesh, INDIA
  • Abhishek Kumar Department of Pharmacy, College of Pharmacy, Agra, Uttar Pradesh, INDIA
  • Ankit Kumar Faculty of Pharmacy, Agrawan Heritage University, Agra, Uttar Pradesh, INDIA
  • Sanjeev Kumar Faculty of Pharmacy, Agrawan Heritage University, Agra, Uttar Pradesh, INDIA

DOI:

https://doi.org/10.55544/jrasb.4.5.4

Keywords:

Nrf2–Keap1 pathway, Oxidative stress, Diabetes mellitus, Diabetic complications, Mitochondrial dysfunction, Antioxidant defense, Inflammation and redox signalling, Pharmacological modulation of Nrf2, Natural Nrf2 activators, Bardoxolone methyl, Metabolic regulation in diabetes, SGLT2 inhibitors, GLP-1 receptor agonists

Abstract

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.

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2025-10-24

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Saxena, A., Saxena, S., Saxena, Y., Jain, A., Chaudhary, R., Bharti, P., … Kumar, S. (2025). Pharmacological Modulation of the Nrf2–Keap1 Pathway in Diabetes: Mechanisms, Therapeutic Advances, and Future Directions. Journal for Research in Applied Sciences and Biotechnology, 4(5), 38–63. https://doi.org/10.55544/jrasb.4.5.4

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Copyright (c) 2025 Amar Saxena, Shrestha Saxena, Yash Saxena, Ashita Jain, Rama Chaudhary, Pooja Bharti, Shivdeep Mishra, Chandrabhan Singh, Abhishek Kumar, Ankit Kumar, Sanjeev Kumar

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