Zeng M, Li Q, Li L, Xiang CF, Wang YJ. Melatonin regulates Sirt1/Nrf2/GPX4 pathway to inhibit ferroptosis and alleviate myocardial injury caused by sepsis. World J Cardiol 2026; 18(2): 113358 [DOI: 10.4330/wjc.v18.i2.113358]
Corresponding Author of This Article
Yi-Jun Wang, Research Fellow, Department of Emergency, The First People’s Hospital of Chenzhou, No. 108 Luojiajing Street, Chenzhou 423000, Hunan Province, China. wangyijun202507@163.com
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Cardiac & Cardiovascular Systems
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Basic Study
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Feb 26, 2026 (publication date) through Feb 9, 2026
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World Journal of Cardiology
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1949-8462
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Zeng M, Li Q, Li L, Xiang CF, Wang YJ. Melatonin regulates Sirt1/Nrf2/GPX4 pathway to inhibit ferroptosis and alleviate myocardial injury caused by sepsis. World J Cardiol 2026; 18(2): 113358 [DOI: 10.4330/wjc.v18.i2.113358]
World J Cardiol. Feb 26, 2026; 18(2): 113358 Published online Feb 26, 2026. doi: 10.4330/wjc.v18.i2.113358
Melatonin regulates Sirt1/Nrf2/GPX4 pathway to inhibit ferroptosis and alleviate myocardial injury caused by sepsis
Min Zeng, Qiong Li, Lin Li, Cheng-Fang Xiang, Yi-Jun Wang
Min Zeng, Lin Li, Cheng-Fang Xiang, Yi-Jun Wang, Department of Emergency, The First People’s Hospital of Chenzhou, Chenzhou 423000, Hunan Province, China
Min Zeng, Jinan University, Guangzhou 51063, Guangdong Province, China
Qiong Li, Institute of Critical Care Medicine, The First People’s Hospital of Chenzhou, Chenzhou 423000, Hunan Province, China
Author contributions: Zeng M and Wang YJ were responsible for conceptualization, writing original draft, review and editing; Li Q and Li L were responsible for data curation; Li Q, Li L, and Xiang CF were responsible for formal analysis; all authors read and approved the final manuscript.
Supported by 2025 Hunan Provincial Natural Science Foundation Regional Joint Fund, No. 2025JJ70596.
Institutional animal care and use committee statement: The animal experiments described in this study were authorized and approved by the experimental animal Ethics Committee of Guangdong Provincial Medical Experimental Animal Center (No. D202404-12), and conducted in compliance with the institutional guidelines (Directive 2010/63/EU in Europe) for the care and use of animals.
Conflict-of-interest statement: The authors declare that they have no competing interests regarding the publication of this paper.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The data used to support the findings of this study are available from the corresponding author upon request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yi-Jun Wang, Research Fellow, Department of Emergency, The First People’s Hospital of Chenzhou, No. 108 Luojiajing Street, Chenzhou 423000, Hunan Province, China. wangyijun202507@163.com
Received: August 25, 2025 Revised: September 28, 2025 Accepted: November 28, 2025 Published online: February 26, 2026 Processing time: 170 Days and 20.5 Hours
Abstract
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.
Core Tip: Sepsis often results in myocardial injury, a major cause of death in affected patients. In this study, we demonstrated that melatonin, an endogenous hormone with antioxidant and anti-inflammatory properties, protects against sepsis-induced myocardial injury. Using both a mouse model and HL-1 cardiomyocytes, we found that melatonin improved cardiac function, reduced oxidative stress, and inhibited ferroptosis by activating the sirtuin 1/nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4 pathway. These findings provide novel mechanistic insights and highlight the therapeutic potential of melatonin for septic myocardial injury.
