Melatonin and Diabetic Nephropathy: From Mechanistic Pathways to Translational Opportunities in Clinical Management.

Abstract

Introduction/objective: Diabetic Nephropathy (DN) remains a leading cause of end-stage renal disease worldwide, characterized by a complex interplay of oxidative stress, chronic inflammation, and circadian rhythm disruption. Despite standard-of-care treatments like RAS inhibitors and newer agents like SGLT2 inhibitors and GLP-1 receptor agonists, a significant residual risk for renal progression persists. Melatonin, a pleiotropic pineal hormone, has emerged as a potential adjunctive therapy due to its potent antioxidant and anti-inflammatory properties. This article is a narrative review, incorporating elements of a systematic literature-search strategy, and aims to synthesize the molecular mechanisms of melatonin in DN, evaluate the current preclinical and clinical evidence for its efficacy, and discuss its potential integration into precision-based treatment protocols.

Methods: A comprehensive search of electronic databases (PubMed, Scopus, Web of Science) was conducted to identify relevant preclinical and clinical studies published through mid-2025 focusing on melatonin's role in DN and its interaction with standard therapies.

Results: Preclinical evidence robustly demonstrates that melatonin mitigates renal injury by inhibiting NF-κB-mediated inflammation, activating Nrf2-driven antioxidant defenses, and restoring SIRT1-mediated mitophagy to preserve mitochondrial function. Emerging clinical data suggest that melatonin may improve markers of insulin resistance and oxidative stress; however, its metabolic effects are context-dependent and influenced by genetic variants. Furthermore, melatonin shows potential synergistic effects when combined with SGLT2 inhibitors and GLP-1 receptor agonists in animal models.

Discussion: The available findings support the potential of melatonin as an adjunctive approach in DN by targeting interconnected oxidative, inflammatory, mitochondrial, and circadian mechanisms. However, the current evidence base remains predominantly preclinical, and clinical evidence is still limited.

Conclusion: Melatonin represents a promising adjunctive agent for DN. However, translating its experimental success to clinical practice requires well-powered, multicenter trials. Future research should prioritize precision trial designs using molecular biomarkers and chronotherapeutic dosing to optimize therapeutic outcomes and long-term safety.