Semaglutide, a novel analog of glucagon-like peptide-1 (GLP-1), has shown potential therapeutic benefits for cardiac function. This study aimed to investigate the efficacy of semaglutide in mitigating doxorubicin-induced cardiotoxicity. Doxorubicin, a potent chemotherapeutic agent, is known for its cardiotoxic effects, which can lead to irreversible cardiac dysfunction and heart failure. The study used a mouse model of chronic doxorubicin-induced myocardial injury and found that semaglutide significantly improved cardiac function, reduced myocardial damage, and attenuated mitochondrial dysfunction. RNA sequencing identified Bnip3 as a key gene mediating the protective effect of semaglutide. Overexpression of Bnip3 in the heart prevented the improvement in cardiac function caused by semaglutide. In vitro experiments showed that semaglutide reduced Bnip3 expression in mitochondria via the PI3K/AKT pathway, improving mitochondrial function. The study concluded that semaglutide ameliorates doxorubicin-induced mitochondrial and cardiac dysfunction by reducing Bnip3 expression in mitochondria, thereby improving mitochondrial function and reducing cardiac injury. This suggests that semaglutide could be a potential therapy for reducing doxorubicin-induced acute cardiotoxicity.Semaglutide, a novel analog of glucagon-like peptide-1 (GLP-1), has shown potential therapeutic benefits for cardiac function. This study aimed to investigate the efficacy of semaglutide in mitigating doxorubicin-induced cardiotoxicity. Doxorubicin, a potent chemotherapeutic agent, is known for its cardiotoxic effects, which can lead to irreversible cardiac dysfunction and heart failure. The study used a mouse model of chronic doxorubicin-induced myocardial injury and found that semaglutide significantly improved cardiac function, reduced myocardial damage, and attenuated mitochondrial dysfunction. RNA sequencing identified Bnip3 as a key gene mediating the protective effect of semaglutide. Overexpression of Bnip3 in the heart prevented the improvement in cardiac function caused by semaglutide. In vitro experiments showed that semaglutide reduced Bnip3 expression in mitochondria via the PI3K/AKT pathway, improving mitochondrial function. The study concluded that semaglutide ameliorates doxorubicin-induced mitochondrial and cardiac dysfunction by reducing Bnip3 expression in mitochondria, thereby improving mitochondrial function and reducing cardiac injury. This suggests that semaglutide could be a potential therapy for reducing doxorubicin-induced acute cardiotoxicity.