摘要Astragali Radix(AR),a traditional Chinese medicine(TCM),has demonstrated therapeutic ef-ficacy against various diseases,including cardiovascular conditions,over centuries of use.While doxorubicin serves as an effective chemotherapeutic agent against multiple cancers,its clinical application remains constrained by significant cardiotoxicity.Research has indicated that AR exhibits protective properties against doxorubicin-induced cardiomyopathy(DIC);however,the specific bioactive components and underlying mechanisms responsible for this therapeutic effect remain incompletely understood.This investigation seeks to identify the protective bioactive components in AR against DIC and elucidate their mechanisms of action.Through network medicine analysis,astragaloside Ⅳ(AsⅣ)and formononetin(FMT)were identified as potential cardioprotective agents from 129 AR components.In vitro experiments using H9c2 rat cardiomyocytes revealed that the AsⅣ-FMT combination(AFC)effectively re-duced doxorubicin-induced cell death in a dose-dependent manner,with optimal efficacy at a 1∶2 ratio.In vivo,AFC enhanced survival rates and improved cardiac function in both acute and chronic DIC mouse models.Additionally,AFC demonstrated cardiac protection while maintaining doxorubicin's anti-cancer efficacy in a breast cancer mouse model.Lipidomic and metabolomics analyses revealed that AFC normalized doxorubicin-induced lipid profile alter-ations,particularly by reducing fatty acid accumulation.Gene knockdown studies and inhibit-or experiments in H9c2 cells demonstrated that AsⅣ and FMT upregulated peroxisome prolif-erator activated receptor γ coactivator 1α(PGC-1α)and PPARα,respectively,two key pro-teins involved in fatty acid metabolism.This research establishes AFC as a promising thera-peutic approach for DIC,highlighting the significance of multi-target therapies derived from natural herbals in contemporary medicine.