Melatonin as a Multi-Target Therapeutic Strategy for Sepsis-Associated Acute Kidney Injury: Mechanistic Insights and Translational Perspectives

Abstract

Context: Sepsis-associated acute kidney injury (SA-AKI) is a frequent and life-threatening complication of sepsis that increases mortality, prolongs stays in the intensive care unit, and raises healthcare costs. Despite advances in supportive care, no pharmacological therapy has consistently prevented or reversed SA-AKI. Mitochondrial dysfunction, oxidative stress, excessive inflammation, and regulated cell death are central to its pathogenesis. Melatonin, an endogenous indoleamine with potent antioxidant and immunomodulatory properties, has emerged as a promising multi-target therapeutic candidate. This review summarizes current experimental and emerging clinical evidence on the renoprotective effects and molecular mechanisms of melatonin in SA-AKI. Evidence Acquisition: A structured narrative review was conducted using a predefined, nonsystematic literature search of PubMed/MEDLINE and Google Scholar from database inception through January 31, 2026. Original experimental and clinical studies evaluating melatonin or melatonergic agents in SA-AKI were included. Two reviewers independently screened the studies, with disagreements resolved by consensus. Findings were synthesized narratively because of substantial heterogeneity. Results: Ten eligible studies, predominantly involving rodent models of sepsis induced by lipopolysaccharide or cecal ligation and puncture, were included. Melatonin consistently improved renal function and histopathological outcomes while reducing oxidative stress and inflammation. Mechanistically, it preserved mitochondrial integrity by enhancing mitophagy through the PTEN-induced kinase 1 (PINK1)/Parkin and SIRT3–mitochondrial transcription factor A (TFAM) pathways and by suppressing cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING), nuclear factor kappa B (NF-κB), and NOD-like receptor protein 3 (NLRP3) inflammasome signaling. Additional protective effects included activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and inhibition of apoptosis and ferroptosis. Combination therapy with mesenchymal stem cells or ascorbic acid showed additive benefits in preclinical studies. Conclusions: Current evidence supports melatonin as a biologically plausible, multitarget therapeutic candidate for SA-AKI. However, robust clinical trials are needed to establish its optimal dose, timing, safety, and efficacy in patients.