ABSTRACT: Sepsis-induced cardiomyopathy (SIC) is one of the most common complications of infection-induced sepsis. An imbalance in inflammatory mediators is the main factor leading to SIC. N-methyladenosine (mA) is closely related to the occurrence and development of sepsis. N-methyladenosine reader YTH domain containing 1 (YTHDC1) is an mA N-methyladenosine recognition protein. However, the role of YTHDC1 in SIC remains unclear. Herein, we demonstrated that YTHDC1-shRNA inhibits inflammation, reduces inflammatory mediators, and improves cardiac function in a LPS-induced SIC mouse model. Based on the Gene Expression Omnibus database analysis, serine protease inhibitor A3N is a differential gene of SIC. Furthermore, RNA immunoprecipitation indicated that serine protease inhibitor A3N (SERPINA3N) mRNA can bind to YTHDC1, which regulates the expression of SERPINA3N. Serine protease inhibitor A3N–siRNA reduced LPS-induced inflammation of cardiac myocytes. In conclusion, the mA reader YTHDC1 regulates SERPINA3N mRNA expression to mediate the levels of inflammation in SIC. Such findings add to the relationship between mA reader YTHDC1 and SIC, providing a new research avenue for the therapeutic mechanism of SIC.