Melatonin regulates Sirt1/Nrf2/GPX4 pathway to inhibit ferroptosis and alleviate myocardial injury caused by sepsis.

BACKGROUND: Sepsis, a common and severe infectious disease, remains one of the leading causes of mortality among patients, with myocardial injury representing a major contributor to adverse outcomes. Melatonin, an endogenous hormone, is known to regulate oxidative stress and inflammatory responses; however, its specific role in sepsis-induced myocardial injury remains unclear. AIM: To investigate the protective effects of melatonin on sepsis-induced myocardial injury and to elucidate the underlying mechanisms with a focus on the sirtuin 1/nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4 pathway. METHODS: Male 57BL/6 mice were assigned to four groups: (1) The control group; (2) The lipopolysaccharide (LPS) group (15 mg/kg); (3) The LPS plus ferrostatin-1 group (ferroptosis inhibitor, 5 mg/kg); and (4) The LPS plus melatonin group (10 mg/kg). Cardiac function, myocardial injury, biochemical markers, and protein expression levels were evaluated using echocardiography, hematoxylin and eosin staining, biochemical assay kits, western blotting, and the cell counting kit-8 assay. To further investigate the effects of melatonin in vitro, HL-1 cardiomyocytes were subjected to the same treatment conditions. RESULTS: Echocardiography and histological evaluation revealed significant impairments in cardiac function and marked myocardial tissue damage in the LPS group, whereas these pathological changes were alleviated in the LPS plus melatonin group. Treatment with melatonin significantly reduced serum levels of brain natriuretic peptide, lactate dehydrogenase, creatine kinase-MB, and cardiac troponin I, while improving myocardial reactive oxygen species and glutathione levels as well as superoxide dismutase activity compared with the LPS group. Protein expression analysis demonstrated an increase in glutathione peroxidase 4 and a decrease in NADPH oxidase 4 and acyl-CoA synthetase long-chain family member 4, consistent with reduced oxidative stress and ferroptosis. In addition, cell viability assays confirmed that melatonin effectively protected HL-1 cardiomyocytes from LPS-induced cytotoxicity. CONCLUSION: The findings indicate that melatonin alleviates sepsis-induced myocardial injury by inhibiting ferroptosis through regulation of the sirtuin 1/nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4 pathway, providing evidence supporting the potential use of melatonin in the treatment of sepsis-related myocardial injury.