BACKGROUNDSepsis-induced cardiomyopathy often leads to bad prognosis of patients, and even death. However, there is no effective therapeutic strategies for sepsis-caused cardiomyopathy. GYY4137 has positive therapeutic effects in many diseases. The aim of this study was to explore the mechanism underlying the sepsis-induced cardiomyopathy and investigate the protective role of the hydrogen sulfide (H2S) donor GYY4137 in sepsis-induced cardiomyopathy.METHODSGYY4137 was administrated in mouse model of sepsis-induced cardiomyopathy (SICM) was generated by cecum ligation and puncture (CLP), and then plasma levels of hydrogen sulfide and cytokines were measured, and inflammatory cell infiltration in myocardial tissue was determined by immunohistochemistry and immunofluorescence staining. RNA sequencing assay was performed to monitor the RNA expression profile. RESULTSH2S levels were reduced in the serum of sepsis-molded mice, GYY4137 reduced macrophage infiltration in the sepsis model. RNA-seq suggested that GYY4137 has an important role in inflammatory regulation. Hydrogen sulfide can inhibit NLRP3 inflammasome activity in macrophages and reduce the secretion of inflammatory factors, while GYY4137 can reduce the production of reactive oxygen species in cardiomyocytes, thus exerting a protective effect on the myocardium.CONCLUSIONGYY4137 can reduce myocardial injury in sepsis by inhibiting the inflammatory response and reducing the production of myocardial reactive oxygen species. It can provide new therapeutic ideas for clinical practice.