melatonin

Overview

Melatonin is an indoleamine best known as a regulator of circadian rhythms and sleep-wake timing, but it is also studied as a pleiotropic bioactive molecule with antioxidant, anti-inflammatory, and mitochondria-modulating properties. In biomedical research, it is frequently discussed as a therapeutic candidate rather than only as an endogenous hormone, particularly in contexts where oxidative stress, inflammation, metabolic dysfunction, and mitochondrial injury contribute to disease.

Recent work has examined melatonin across a broad range of conditions, including type 2 diabetes, polycystic ovary syndrome, osteoporosis, pulmonary arterial hypertension, metabolic syndrome-associated tissue injury, Parkinson’s disease-related biomarker patterns, and age-related ovarian and stem-cell dysfunction. Mechanistically, these studies place melatonin in pathways involving sirtuin 1, NRF2, mitophagy, mitochondrial fission, RANKL/OPG signaling, and inflammatory mediators such as interleukin-6 and tumour necrosis factor-α. It has also been considered alongside other agents such as quercetin, resveratrol, sirolimus, cholecalciferol, ubidecarenone, and Insulin Therapy in translational and preclinical settings.

Focus of Latest Publications

Recent research demonstrates melatonin's neuroprotective and anti-inflammatory mechanisms across multiple disease models. In an aluminum-induced rat model of Alzheimer's disease, melatonin treatment significantly improved learning and memory performance on the Morris water maze test and reduced plasma levels of interleukin-6 and tumor necrosis factor alpha. Immunohistochemical analysis showed melatonin increased neuronal marker expression while reducing microglial activation and inflammatory markers in the frontal cortex. To address melatonin's low bioavailability and slow onset of action when treating insomnia, investigators developed dissolving microneedle arrays for transdermal delivery, achieving rapid systemic absorption and central nervous system penetration in mouse models. Metabolomic studies in Parkinson's disease identified melatonin among metabolites with distinct secretion patterns across patient clusters, suggesting heterogeneous roles in disease pathophysiology.

The emerging mechanistic literature reveals melatonin's effects on mitochondrial quality control and cellular aging. In human adipose-derived mesenchymal stem cells under oxidative stress, melatonin treatment restored mitochondrial membrane potential, reduced reactive oxygen species accumulation, and upregulated mitophagy markers including Parkin, BNIP3, and LC3B, offering potential to reverse stem cell senescence. In a dihydrotestosterone-induced polycystic ovary syndrome model, melatonin attenuated excessive Drp1-mediated mitochondrial fission in granulosa cells through sirtuin 1 upregulation, restoring mitochondrial morphology and function. In high-glucose environments relevant to diabetes, melatonin enhanced osteogenic differentiation of bone marrow mesenchymal stem cells by activating NRF2 and promoting autophagy through regulated macrophage-stem cell interactions.

Across multiple metabolic and inflammatory conditions, melatonin demonstrated protective effects on tissue damage and inflammatory pathways. In diabetic rats, melatonin alone or combined with quercetin reduced hepatic oxidative stress, normalized elevated liver enzymes, and modulated inflammatory cytokines. In rats with concurrent metabolic syndrome and periodontal disease—conditions that synergistically amplify inflammation—melatonin ameliorated metabolic parameters, preserved periodontal bone, restored hepatic histology, and modulated inflammation by decreasing NOD-like receptor pyrin domain-containing 3 activation while restoring interleukin-10 expression. In ovariectomy-induced osteoporosis, melatonin enhanced bone strength, inhibited osteoclast differentiation, increased type I collagen expression, and suppressed the RANKL/OPG axis while promoting Wnt/β-catenin signaling. Novel melatonin analogs optimized for membrane permeability demonstrated enhanced nasal absorption and prolonged brain retention with improved sleep efficacy.

Comparative efficacy studies and emerging safety signals contextualize melatonin's therapeutic potential. In monocrotaline-induced pulmonary arterial hypertension, melatonin produced antioxidant and anti-inflammatory effects comparable to sildenafil, improving right ventricular contractility and reducing lipid peroxidation. However, a recent electronic health record study raised concerns regarding a potential heart failure safety signal associated with long-term melatonin use in adults with insomnia, indicating the need for further investigation of cardiovascular effects in clinical populations.

Key Publications

• NEWJul The protective role of melatonin on the brain in a rat model of Alzheimer's disease. (Metabolic brain disease, 2026, PMID 42384283): "Melatonin (Mel) is a neurohormone that regulates circadian rhythm and possesses antioxidant, anti-inflammatory and neuroprotective properties."
• NEWJun Biomedical publication details. (PubMed Database, 2026, PMID 42306921)
• May Melatonin and cardiovascular risk: an NHANES reality check after recent heart failure concerns. (Open heart, 2026, PMID 42167796): "A large electronic health record study presented at the American Heart Association Scientific Sessions 2025 reported a heart failure safety signal associated with long-term melatonin use among adults with insomnia."
• May Melatonin protects liver and periodontal tissues from inflammation exacerbated by metabolic syndrome-periodontitis association. (Journal of molecular medicine (Berlin, Germany), 2026, PMID 42154263): "...examines melatonin (MEL) as a therapeutic agent."
• May Melatonin improves osteogenic differentiation in a high-glucose environment by activating NRF2 to promote autophagy through the regulation of cross-talk between macrophages and bone marrow mesenchymal stem cells. (Inflammation research : official journal of the European Histamine Research Society ... [et al.], 2026, PMID 42096091): "Melatonin (MT) can regulate the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), but its effect on the osteogenic differentiation of BMSCs under high glucose (HG) conditions is unclear."
• May Melatonin and Coenzyme Q10 mitigate Senescence in Human Adipose-Derived Mesenchymal Stem Cells by Restoring Mitophagy and Mitochondrial Proteostasis. (PloS one, 2026, PMID 42054487): "This study explores mitophagy's role in regulating senescence in human adipose-derived mesenchymal stem cells (HADMSCs) and evaluates the therapeutic potentiality of antioxidants-melatonin and coenzyme Q10 (CoQ10) targeting mitochondria."
• May Melatonin and Quercetin Co-Treatment Attenuates Hepatic Damage in Diabetic Rats by Mitigating Oxidative Stress and Inflammation. (Journal of biochemical and molecular toxicology, 2026, PMID 42021540): "We analyzed the effect of treatment with quercetin and melatonin on the liver of diabetic rats."
• May The molecular mechanism of melatonin in regulating osteoporosis based on the RANKL/OPG signaling axis. (Journal of molecular endocrinology, 2026, PMID 42023609): "Melatonin is a promising drug for improving bone mass in postmenopausal women."
• Apr Personalized metabolite biomarker predictions reveal heterogeneous characteristics of Parkinson's disease. (NPJ Parkinson's disease, 2026, PMID 42014729): "Furthermore, certain metabolites like melatonin, and biliverdin, though not identified by the consensus approach, showed distinct secretion patterns across patient clusters."
• May Melatonin attenuates Drp1-mediated excessive mitochondrial fission through upregulation of SIRT1 in granulosa cells in polycystic ovary syndrome. (Reproduction (Cambridge, England), 2026, PMID 41949882): "This study elucidates the mechanism by which melatonin ameliorates mitochondrial function in polycystic ovary syndrome by suppressing excessive mitochondrial fission."