ABSTRACT: Objective To study the effects of different processing methods of Zhigancao Decoction on myocardial fibrosis and their mechanisms. Methods Thirty-two mice were randomly assigned to four groups:blank,model,ethanol-decocted,and water-decocted groups.High-performance liquid chromatography(HPLC)was used to select two processing methods with different contents of marker components(ammonium glycyrrhizinate and ginsenoside Rg1).The mice were then gavaged with the corresponding decoctions for 14 days.After treatment,biological indicators and cardiac tissue metabolomics data were analyzed. Results Both ethanol-decocted and water-decocted Zhigancao Decoctions improved myocardial inflammation and structure,reduced the elevated heart weight index(P<0.05),and down regulated collagen synthesis marker PⅢNP. However, they did not significantly improve cardiac function indicators(EF,FS,cTnI).Metabolomics identified 18 differential metabolites and 11 pathways. Conclusion Zhigancao Decoctions prepared by different methods have varying marker component levels. Both inhibit collagen deposition in ISO-induced myocardial fibrosis and affect myocardial metabolites, but show no significant difference in therapeutic efficacy, likely due to the effective threshold of the marker components.