Xanthosine alleviates myocardial ischemia-reperfusion injury through attenuation of cardiomyocyte ferroptosis

  • Cell Mol Biol Lett. 2025 Jul 28;30(1):93. doi: 10.1186/s11658-025-00766-y.
Yang Xu  #  1 ,  Wenfeng Zhou  #  1 ,  Zhongguo Fan  #  1 ,  Yiwei Cheng  #  2  3 ,  Yujia Xiao  1 ,  Yu Liu  4 ,  Xinxin Li  1 ,  Zhenjun Ji  1 ,  Yi Fan  5  6 ,  Genshan Ma  7
Affiliations
  • 1. Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
  • 2. State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, China.
  • 3. Innovation Center of Suzhou, Nanjing Medical University, Suzhou, China.
  • 4. Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
  • 5. Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China. [email protected].
  • 6. Department of Cell and Regenerative Biology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, 53705, USA. [email protected].
  • 7. Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 40722060 DOI: 10.1186/s11658-025-00766-y
Abstract

Background: Ischemic heart disease remains a leading cause of morbidity and mortality worldwide, with myocardial ischemia-reperfusion (I/R) injury significantly contributing to cardiomyocyte death and poor outcomes post-acute myocardial infarction (AMI). Emerging evidence highlights metabolic changes during myocardial injury, particularly in purine metabolism. This study investigates the protective role of xanthosine (XTS), a purine metabolism intermediate, in alleviating I/R injury.

Methods: Neonatal and adult mouse myocardial tissues post-myocardial infarction (MI) were analyzed using untargeted and targeted metabolomics to explore metabolic profiles. The effects of XTS on I/R injury were evaluated in vivo using a murine I/R model and in vitro with hypoxia/reoxygenation-treated neonatal rat cardiomyocytes (NRCMs). Cardiac function, fibrosis, Apoptosis, oxidative stress markers, and ferroptosis-related pathways were assessed via echocardiography, biochemical assays, western blotting, and electron microscopy. Integrated drug affinity responsive target stability (DARTS)-based drug target screening and RNA-seq transcriptomic profiling elucidate XTS-mediated mechanisms against I/R injury.

Results: Metabolomics revealed distinct differences in purine metabolism between neonatal and adult mice post-MI, with significant XTS accumulation observed in neonatal hearts. In vivo, XTS treatment in adult mice enhanced left ventricular function, reduced fibrosis, and alleviated lipid peroxidation and mitochondrial damage post-I/R injury. In vitro, XTS significantly improved cardiomyocyte viability, reduced oxidative stress, and mitigated Ferroptosis by restoring Glutathione Peroxidase 4 (GPX4) levels and reducing acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) expression. Mechanistically, XTS stabilized metabolic Enzymes, upregulated L-arginine and glutathione (GSH) to mitigate Reactive Oxygen Species(ROS), and inhibited Ferroptosis.

Conclusions: XTS, a key purine metabolism intermediate, improves cardiac remodeling and function following I/R injury by suppressing Ferroptosis and reducing mitochondrial ROS production. These findings provide novel insights into the therapeutic potential of XTS as an adjunctive treatment for patients with AMI undergoing revascularization.

Keywords
Ferroptosis; Ischemia–reperfusion (I/R) Injury; Purine metabolism; Reactive oxygen species (ROS); Xanthosine (XTS).
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