ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1653738
This article is part of the Research TopicExploring Cardiovascular and Cerebrovascular Diseases Interaction with Inflammation: Biomarkers, Drug Targets, and Personalized Treatments through Multi-omics Data Integration, Volume IIView all 3 articles
Xrcc6 coordinates cardiomyocyte repair and immune regulation in myocardial ischemia-reperfusion injury: Fisetin as a therapeutic modulator
Provisionally accepted
YiJie He1,2,3
Jin Li1,2,3Linlong Guo1,2Mu Chen1,2
Haiqing Pan1,2Zhanqing Li1,2
Hua Tian1,2Huan Yu1,2
Zhou Yuhong1,2*
Hongwen Xiao1,2*- 1Department of Basic Medicine, Key laboratory of functional and clinical translational medicine, Xiamen Medical College, Xiamen, Fujian 361023, China
- 2Department of Basic Medicine, Institute of Respiratory Diseases Xiamen Medical College of Respiratory Diseases, Xiamen Medical College, Xiamen, Fujian 361023, China
- 3Harbin Medical University, Harbin, China
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Myocardial ischemia-reperfusion (I/R) injury remains a major challenge in ischemic heart disease treatment. Our study elucidates the role of the DNA damage repair gene Xrcc6 in myocardial I/R injury and evaluates the cardioprotective effects of the natural flavonoid Fisetin. However, the molecular mechanisms of Fisetin via Xrcc6-targeted modulation are unclear. We integrated bulk and single-cell RNA sequencing to analyze cardiomyocyte subtypes and gene expression profiles, identifying key co-expression modules through high-dimensional weighted gene co-expression network analysis (hdWGCNA). Trajectory inference and intercellular communication analysis revealed cell fate dynamics and immune regulatory mechanisms, while molecular docking and dynamics simulations confirmed Fisetin's stable binding to Xrcc6 (binding free energy: −7.55kcal/mol). Transcriptomics showed significant Xrcc6 downregulation post-I/R, with single-cell data highlighting vCMs3 as a reparative cardiomyocyte subtype whose proportion correlated with Xrcc6 expression. Pseudotime analysis positioned vCMs3 at early differentiation stages, with dynamic Xrcc6 expression along the trajectory. CIBERSORT and CellChat linked Xrcc6 to macrophage polarization. In vivo experiments confirmed that Fisetin's cardioprotection is mediated by Xrcc6 upregulation, which attenuates DNA damage (γH2A.X suppression) and modulates the inflammatory response, ultimately improving cardiac function. This study pioneers Xrcc6's dual role in cardiomyocyte fate and immune regulation during I/R injury and establishes Fisetin as a Xrcc6-targeted therapeutic candidate, offering novel mechanistic insights for I/R injury intervention.
Keywords: Ischemia-reperfusion, XRCC6, Fisetin, molecular dynamics, DNA Damage
Received: 25 Jun 2025; Accepted: 26 Aug 2025.
Copyright: © 2025 He, Li, Guo, Chen, Pan, Li, Tian, Yu, Yuhong and Xiao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Zhou Yuhong, Department of Basic Medicine, Key laboratory of functional and clinical translational medicine, Xiamen Medical College, Xiamen, Fujian 361023, China
Hongwen Xiao, Department of Basic Medicine, Key laboratory of functional and clinical translational medicine, Xiamen Medical College, Xiamen, Fujian 361023, China
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