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[Display omitted] The cardiotoxicity of trastuzumab (TRZ) seriously affects the prognosis of breast cancer patients, but the underlying mechanisms remains to be elucidated. This study aimed to investigate the potential molecular mechanisms of TRZ-induced cardiotoxicity based on RNA sequencing (RNA-Seq) and bioinformatics analysis. Kunming mice were exposed to 10 mg/kg TRZ for 6 and 10 days, followed by echocardiography, histopathology and serum biochemical analysis to evaluate the cardiotoxicity model. The results showed no significant changes after 6 days administration of TRZ. After 10 days administration of TRZ, the mice showed cardiac dysfunction, myocardial injury and fibrosis, and the serum levels of LDH, CK, CK-MB and cTnI were increased compared to the control [CON (Day 10)] group, indicating the cardiotoxicity model was successfully established. We compared gene expression levels in mice cardiac tissues by RNA-Seq and screened out 593 differentially expressed genes (DEGs). Results based on Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein–protein interaction (PPI) network analysis and RT-PCR revealed that the CD74/STAT1 signaling pathway might play an important role in TRZ-induced cardiotoxicity. In the TRZ group, the protein expressions of CD74, p-STAT1 (Tyr) and p-STAT1 (Ser) were increased. The TUNEL staining showed increased apoptosis of cardiomyocytes. In addition, an increased expressions of Bax, Caspase-3, IFN-γ and TNF-α and a decreased expression of Bcl-2 were observed in Western blot results, indicating the apoptosis and inflammation levels were increased. These findings suggested that TRZ may induce cardiotoxicity in mice by activating the CD74/STAT1 signaling pathway, which might be related to the induction of apoptosis and inflammation. [ABSTRACT FROM AUTHOR]