BACKGROUND: Septic cardiomyopathy is a frequent complication in patients with sepsis and is associated with a high mortality rate. Given its clinical significance, understanding the precise underlying mechanism is of great value. METHODS AND RESULTS: Our results unveiled that Z-DNA binding protein 1 (ZBP1) is upregulated in myocardial tissues of lipopolysaccharide (LPS)-treated mice. Single-cell mRNA sequencing (scRNA-seq) and single-nucleus mRNA sequencing (snRNA-seq) indicated that Zbp1 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-treated mice. Mechanistically, snRNA-seq showed that ZBP1 is mainly expressed in macrophages and deletion of ZBP1 promotes the macrophage polarisation towards M2-subtype, which reduces inflammatory cell infiltration. Notably, myeloid-specific deficiency of ZBP1 also promotes M2 macrophage polarisation and improves cardiac dysfunction, validating the role of macrophage-derived 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-treated mice. CONCLUSIONS: Our study provides evidence of a novel STAT1-ZBP1 axis in macrophage promoting septic cardiomyopathy, and underscores the potential of macrophage-derived ZBP1 as a therapeutic target for septic cardiomyopathy. KEY POINTS: Macrophage-derivedZBP1 exacerbates LPS-induced myocardial dysfunction and inflammatory cellinfiltration. Deletionof ZBP1 promotes macrophage polarisation from M1 to M2. STAT1-ZBP1axis promotes septic cardiomyopathy. ZBP1has emerged as a potential therapeutic target for inflammationand septic cardiomyopathy.