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Given its clinical significance, understanding the precise underlying mechanism is of great value.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>Our results unveiled that Z\u2010DNA binding protein 1 (ZBP1) is upregulated in myocardial tissues of lipopolysaccharide (LPS)\u2010treated mice. Single\u2010cell mRNA sequencing (scRNA\u2010seq) and single\u2010nucleus mRNA sequencing (snRNA\u2010seq) indicated that <jats:italic>Zbp1<\/jats:italic> mRNA in endothelial cells, fibroblasts and macrophages appeared to be elevated by LPS, which is partially consistent with the results of immunofluorescence. Through echocardiography, we identified that global deletion of ZBP1 improves cardiac dysfunction and the survival rate of LPS\u2010treated mice. Mechanistically, snRNA\u2010seq showed that ZBP1 is mainly expressed in macrophages and deletion of ZBP1 promotes the macrophage polarisation towards M2\u2010subtype, which reduces inflammatory cell infiltration. Notably, myeloid\u2010specific deficiency of ZBP1 also promotes M2 macrophage polarisation and improves cardiac dysfunction, validating the role of macrophage\u2010derived ZBP1 in septic myocardial dysfunction. Finally, we revealed that LPS increases the transcription and expression of ZBP1 through signal transducer and activator of transcription 1 (STAT1). Fludarabine, the inhibitor of STAT1, could also promote M2 macrophage polarisation and improve cardiac dysfunction of LPS\u2010treated mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study provides evidence of a novel STAT1\u2010ZBP1 axis in macrophage promoting septic cardiomyopathy, and underscores the potential of macrophage\u2010derived ZBP1 as a therapeutic target for septic cardiomyopathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Macrophage\u2010derived ZBP1 exacerbates LPS\u2010induced myocardial dysfunction and inflammatory cell infiltration.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Deletion of ZBP1 promotes macrophage polarisation from M1 to M2.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>STAT1\u2010ZBP1 axis promotes septic cardiomyopathy.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>ZBP1 has emerged as a potential therapeutic target for inflammation and septic cardiomyopathy.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70315","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:50:36Z","timestamp":1745801436000},"source":"Crossref","is-referenced-by-count":13,"title":["Myeloid deficiency of Z\u2010DNA binding protein 1 restricts septic cardiomyopathy via promoting macrophage polarisation towards the M2\u2010subtype"],"prefix":"10.1002","volume":"15","author":[{"given":"Yifan","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Cardiology Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"He","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital Hengyang Medical School University of South China  Hengyang Hunan 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