The breadth of melatonin’s reported activities is striking. Beyond its sedative effect, the review catalogs antitumor, immunomodulatory, antioxidant, antihypertensive and cardioprotective actions, along with roles in regulating body weight, gastrointestinal function, reproduction and thermoregulation. Part of this versatility is chemical: melatonin crosses biological membranes freely and reaches nearly every compartment of the cell. Part of it is signaling: melatonin binds specific G-protein-coupled receptors, but it also engages intracellular pathways that govern whether a cell survives stress, divides, inflames or dies. The question the review tackles is which of these pathways best explains the hormone’s pharmacological reach, and its answer centers on SIRT1, the most intensively studied member of the mammalian sirtuin family.

SIRT1 is a nicotinamide adenine dinucleotide, or NAD+, dependent deacetylase, meaning it removes acetyl chemical groups from proteins only when the metabolic cofactor NAD+ is available. This makes the enzyme a direct sensor of cellular energy status, because NAD+ levels rise and fall with nutrient availability, fasting and metabolic strain. SIRT1 shuttles between the cytoplasm and the nucleus, where it strips acetyl groups from histones, the spools around which DNA is wound, and from a growing list of non-histone proteins including the tumor suppressor p53, the transcription factors FoxO and NF-κB, and the mitochondrial regulator PGC-1α. Through these targets, SIRT1 influences cell survival, metabolism, growth, aging and resistance to stress, which is precisely the portfolio of processes that goes wrong in chronic disease.

The review’s central claim is that melatonin can modulate SIRT1 activity, and that this modulation in turn shapes four fundamental cellular responses: inflammation, oxidative stress, apoptosis and autophagy. In inflammatory bowel disease, for example, recent work cited in the review shows that melatonin restores the intestinal mucosal barrier by activating a SIRT1-LKB1-pAMPK signaling axis. In autoimmune and sepsis models, SIRT1 deacetylates components of the NF-κB pathway and the NLRP3 inflammasome, damping the production of tumor necrosis factor alpha, interleukin-1 and other inflammatory mediators. Because NF-κB sits upstream of cyclooxygenase-2 and inducible nitric oxide synthase, a single deacetylation event can cascade into a broad suppression of the inflammatory program.

The cardiovascular evidence is among the most developed. In type 2 diabetic rats, reduced SIRT1 signaling worsens myocardial ischemia-reperfusion injury, and melatonin treatment restores protection through the enzyme. Melatonin receptor-mediated cardioprotection against ischemia-reperfusion has likewise been traced to SIRT1. In diabetic hearts, melatonin prevents Drp1-mediated mitochondrial fission, the excessive fragmentation of mitochondria that starves cardiomyocytes of energy, via the SIRT1-PGC-1α pathway, and activation of the SIRT1-PGC-1α-SIRT3 cascade protects against mitochondrial dysfunction in isoproterenol-induced myocardial injury. The chemotherapy drug doxorubicin, notorious for causing heart damage, appears less toxic when melatonin activates the Sirt1/Nrf2 pathway, inhibiting oxidative stress, pyroptosis and apoptosis. In sepsis-induced cardiac dysfunction, melatonin acts through SIRT1 to regulate both apoptosis and autophagy, including SIRT1-mediated deacetylation of beclin-1 and of the transcription factor TFEB, which orchestrates lysosomal clearance of damaged material.

The kidney tells a parallel story. Melatonin attenuates acute kidney ischemia-reperfusion injury in diabetic rats by activating the SIRT1/Nrf2/HO-1 axis, a canonical antioxidant pathway in which Nrf2, once deacetylated and stabilized, switches on heme oxygenase-1 and other detoxifying genes. In diabetic kidney disease, protection runs through SIRT1/NLRP3 signaling, curbing the inflammasome-driven inflammation that scars the filtering units of the kidney. Melatonin also prevents acute kidney injury in severely burned rats via SIRT1 activation, and in cadmium-induced proximal tubular injury it preserves mitochondrial function by blocking fission through SIRT1-PGC-1α. Perhaps most intriguingly, melatonin lowers the abundance of hypoxia-inducible factor 1α in human proximal tubular cells by preventing its deacetylation by sirtuin 1, a reminder that SIRT1’s effects are not uniformly protective but context-dependent, and that melatonin’s modulation of the enzyme can push it in either direction depending on the tissue and insult.

In the liver, the review highlights melatonin’s effects on non-alcoholic fatty liver disease, a condition now affecting a substantial share of the world’s overweight and obese population. Melatonin’s benefits in fatty liver models are linked to the microRNA-34a-5p/Sirt1 axis and to autophagy, the cellular recycling system that clears lipid droplets and damaged organelles. In hypercholesterolemic mice, melatonin’s modulation of sirtuin-1 attenuates liver injury. The enzyme also mediates protection against toxic exposures: melatonin inhibits benzo(a)pyrene-induced apoptosis in mouse liver through the miR-34a/Sirt1/autophagy pathway, and it attenuates arsenic-induced liver injury through Nrf2/HO-1, apoptosis and miR-34a/Sirt1/autophagy routes. In alcoholic liver injury, melatonin-induced SIRT1 disrupts the cereblon-YY1-CYP2E1 signaling pathway, reducing the oxidative metabolism of alcohol that generates damaging free radicals, while in sepsis-induced liver injury melatonin activates SIRT1/STAT3 signaling to rescue dysregulated gluconeogenesis.

The reproductive findings may prove the most clinically provocative. In polycystic ovary syndrome, melatonin enhances SIRT1 expression in granulosa cells to ameliorate excessive PINK1/Parkin-mediated mitophagy and to protect mitochondrial membranes through PDK1/Akt signaling, and it attenuates Drp1-driven mitochondrial fission through SIRT1 upregulation. The ROS/SIRT1/STAR axis has been identified as a target through which melatonin corrects atrazine-induced mitochondrial dysfunction and steroid disorders in granulosa cells. In oocytes, melatonin protects against chronic stress-induced meiotic defects by regulating SIRT1, and follicular fluid insufficiency of melatonin has been proposed as a reversible cause of the chromosomal abnormalities seen in oocytes of advanced maternal age. On the male side, melatonin protects mouse testes from palmitic acid-induced lipotoxicity in a SIRT1-dependent manner, ameliorates diabetic impairment of Leydig cell steroidogenic function through SIRT1 activation, and modulates SIRT1 to counter LPS-induced testicular nitro-oxidative stress and inflammation. Human trials add a translational note: melatonin supplementation improved semen parameters in men with idiopathic infertility in a triple-blind randomized placebo-controlled trial, and melatonin therapy added benefit to varicocelectomy in a double-blind trial, with epigenetic effects in a varicocele rat model mediated by silent information regulator 1.

The musculoskeletal section rounds out the picture. In osteoarthritis, melatonin exerts cytoprotective and anti-inflammatory effects in human chondrocyte cells and in rabbit models via the SIRT1 pathway, prevents cartilage matrix degradation by inhibiting NF-κB through SIRT1, and regulates chondrocyte hypertrophy and apoptosis through the Sirt1/P53/P21 axis. It also promotes sirtuin 1 expression to inhibit the IRE1α-XBP1S-CHOP branch of the unfolded protein response, reducing endoplasmic reticulum stress-mediated apoptosis in chondrocytes. In intervertebral disc degeneration, melatonin protects vertebral endplate chondrocytes against apoptosis and calcification via the Sirt1-autophagy pathway and holds promise through inhibiting M1-type macrophage polarization via SIRT1/Notch signaling. Even in cancer the relationship is bidirectional: whereas SIRT1 activation generally protects healthy tissue, melatonin’s antitumor activity in human osteosarcoma cells has been attributed to SIRT1 inhibition, underscoring that the same enzyme can be friend or foe depending on cellular context.

The authors are careful to note the limits of the evidence. Despite the breadth of preclinical data, they write that evidence regarding the role of SIRT1 in melatonin’s effects remains limited, and much of what is known comes from cell cultures and animal models rather than definitive human trials. Whether melatonin reliably activates SIRT1 in human tissues at supplement doses, and whether SIRT1 is necessary rather than merely correlated with the hormone’s benefits, will require pharmacological inhibitors, genetic models and properly powered clinical studies. Still, the synthesis is compelling in its coherence: a hormone produced by a tiny gland in the brain, acting through an NAD+-dependent enzyme that links metabolism to gene expression, appears to coordinate protective programs across organs as different as the heart, kidney, liver, ovary and joint. If future work confirms SIRT1 as the common mediator, melatonin’s humble reputation as a sleep aid may give way to something far more interesting, a cheap and safely tolerated molecule that tunes the body’s central longevity machinery.

Subject of Research: The role of the SIRT1 signaling pathway in the therapeutic effects of melatonin across disease models

Article Title: The therapeutic potential of melatonin: Focus on the SIRT1 signaling pathway

Article References: Vahidinia, Z., Behdarvandy, M., Azami Tameh, A., Barati, S., & Yasamian, A. (2026). The therapeutic potential of melatonin: Focus on the SIRT1 signaling pathway. Molecular Biology Reports, 53(1), Article 1667. https://doi.org/10.1007/s11033-026-12815-6

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12815-6

Keywords: melatonin, SIRT1, sirtuins, NAD+, deacetylation, oxidative stress, autophagy, apoptosis, cardioprotection, diabetic cardiomyopathy, non-alcoholic fatty liver disease, polycystic ovary syndrome