Key Takeaways & Executive Findings
- •• Melatonin reduces oxidative stress and lipid peroxidation in hypoxic cardiomyocytes, inhibiting ferroptosis. • Melatonin improves myocardial infarction size, cardiac injury, and pathological changes in a rat model of AMI. • The cardioprotective effect of melatonin is linked to suppression of iron accumulation and ferroptosis. • Targeting ferroptosis with melatonin may offer a novel therapeutic strategy for acute myocardial infarction.
Abstract
AIM: To investigate whether melatonin can ameliorate acute myocardial infarction (AMI) by inhibiting ferroptosis. METHODS: H9C2 cells were cultured in AnaeroPack system with low sugar and serum-free medium for 10 h to construct a cell model of AMI. Then cells were treated with melatonin and ferroptosis inducer erastin. The cell activity, reactive oxygen species (ROS), lipid peroxidation, mitochondrial membrane potential (MMP), and ferroptosis related protein expression were detected. A rat model of AMI induced by isoprenaline (ISO) injection was established to evaluate the effects of melatonin, in which the myocardial infarction size, cardiac injury, pathological changes, oxidative stress, iron ion and ferroptosis related protein expression were examined. RESULTS: Melatonin decreased the oxidative stress, lipid peroxidation and expression of ferroptosis protein in cardiomyocytes induced by hypoxia, but these effects could be impeded by the ferroptosis inducer erastin. Furthermore, in vivo experiments, we also found that melatonin improved the myocardial infarction size, cardiac injury, pathological changes, oxidative stress, and alleviated iron ion accumulation and ferroptosis. CONCLUSION: The cardioprotective effects of melatonin in AMI are associated with the inhibition of ferroptosis.
1. Introduction
Cardiovascular disease (CVD) is the most common cause of death worldwide and acute myocardial infarction (AMI) is a life-threatening acute CVD [1-3]. AMI is caused by complete occlusion of coronary artery, resulting in myocardial cell ischemia and myocardial necrosis. Although pharmacological thrombolytic therapy and percutaneous coronary intervention (PCI) significantly improve the outcomes for patients with AMI [4-5], 7% of patients die and 22% of survivors may develop chronic heart failure in 1 year after AMI [1]. Therefore, it is urgent to find innovative therapeutic methods for AMI.
Ferroptosis is a mode of programmed cell death caused by iron-dependent lipid peroxidation and the accumulation of reactive oxygen species (ROS) [6]. It is regulated by a variety of cellular metabolic pathways, including redox homeostasis, iron metabolism, mitochondrial activity, and metabolism of amino acids, lipids, and sugars [7-8]. Numerous investigations have shown that the destruction of iron homeostasis can promote the occurrence and development of CVD [7, 9]. In AMI, inhibition of ferroptosis or iron chelation can provide cardioprotective benefits, suggesting that targeting ferroptosis may be a promising novel treatment strategy for AMI [10-11].
Melatonin (Mel) is a main hormone secreted by pineal gland, plays an important role in circadian rhythm regulation, and is a famous antioxidant and free radical scavenger [12-15]. After the concept of ferroptosis was introduced, researchers found that Mel can improve neurodegenerative diseases [16], nonalcoholic fatty liver disease [17], retinal ischemia reperfusion injury [18], acute kidney injury [19], intervertebral disc degeneration and other diseases by inhibiting ferroptosis [20]. Earlier studies have shown that reduced nocturnal Mel levels during AMI are associated with increased oxidative stress [21]. In addition, Mel can protect AMI patients by scavenging free radicals, anti-inflammatory, reducing calcium overload and inhibiting lipid peroxidation [21-23]. The effect of Mel on AMI is closely related to the characteristics of ferroptosis. However, in AMI, there is no clear research revealing that Mel can alleviate AMI by regulating ferroptosis. Therefore, in this study, we explored whether the ameliorative effect of Mel on AMI is connected with ferroptosis.
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HUANG Xiaohui, WEN Weixing, CHEN Peng, LI Weiwen, LI Jiahuan, CAO Yue, HU Yunzhao, HUANG Yuli (2026). Melatonin alleviated acute myocardial infarction by inhibiting ferroptosis. Chinese Journal of Pathophysiology. https://doi.org/10.3969/j.issn.1000-4718.2025.09.002
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Frequently Asked Questions
What is the main finding of this study?
The study demonstrates that melatonin alleviates acute myocardial infarction by inhibiting ferroptosis, a form of iron-dependent cell death.
How was the effect of melatonin tested?
The effect was tested in vitro using H9C2 cardiomyocytes under hypoxic conditions and in vivo using a rat model of AMI induced by isoprenaline injection.
What are the potential clinical implications?
Melatonin could be a novel therapeutic agent for AMI by targeting ferroptosis, potentially reducing myocardial injury and improving outcomes.
What is ferroptosis?
Ferroptosis is a programmed cell death mechanism characterized by iron-dependent lipid peroxidation and accumulation of reactive oxygen species.
How does melatonin inhibit ferroptosis?
Melatonin reduces oxidative stress, lipid peroxidation, and iron accumulation, thereby suppressing ferroptosis in cardiomyocytes.
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