Z-DNA-binding protein 1 exacerbates myocardial ischemia‒reperfusion injury by inducing noncanonical cardiomyocyte PANoptosis

作者：Xiaokai Zhang, Shuai Song, Zihang Huang, Linqi Zeng, Yining Song, Mohan Li, Chenyan Liu, Fengze Cai, Tongyao Wang, Peng Yu, Junbo Ge, Aijun Sun · 发表于：Signal Transduction and Targeted Therapy · 年份：2025 · DOI：10.1038/s41392-025-02430-5 · 被引用次数：29 · 研究领域：PARP inhibition in cancer therapy、Mitochondrial Function and Pathology、Viral Infections and Immunology Research

Myocardial ischemia‒reperfusion (I/R) injury is the primary factor that counteracts the beneficial effects of reperfusion therapy. Cardiomyocyte death serves as the fundamental pathological hallmark of I/R injury. However, targeting a single type of cell death has been reported to be ineffective at preventing I/R injury. ZBP1 is well established as a nucleic acid sensor that activates inflammatory and various cell death signaling pathways. However, the specific role of ZBP1 in adult cardiomyocytes, particularly in the absence of nucleic acid ligands, remains largely unexplored. In this study, our dynamic transcriptomic analyses at various I/R stages revealed a cluster of genes significantly enriched in cell death-related processes, with ZBP1 showing significant expression changes in both our I/R injury mouse model and public human ischemic cardiomyopathy datasets. Cardiomyocytes are the primary cell type expressing ZBP1 in response to I/R injury. Hypoxia/reoxygenation stress induced the upregulation of multiple cell death markers indicative of PANoptosis in adult cardiomyocytes, which was mitigated by ZBP1 deficiency. Compared with treatment with conventional cell death inhibitors, cardiomyocyte-specific Zbp1 deficiency ameliorated I/R-induced PANoptosis, resulting in a more substantial reduction in myocardial infarct size. Conversely, myocardial Zbp1 overexpression in adult mice directly induced cardiac remodeling and heart failure. Mechanistically, ZBP1 drives cardiomyocyte...