The novel combination of astragaloside IV and formononetin protects from doxorubicin-induced cardiomyopathy by enhancing fatty acid metabolism

Astragali Radix (AR) has been used for centuries in traditional Chinese medicine to treat various diseases, including cardiovascular diseases. Doxorubicin is a potent chemotherapy drug known for its efficacy against various cancers, but its use is limited by significant cardiotoxicity. Previous studies have shown a promising protective property of AR against doxorubicin-induced cardiomyopathy (DIC). However, the bioactive components, as well as the mechanism-of-action, contribute to this therapeutic effect remain unclear. This study aims to discover the bioactive components in AR that protect from DIC and understand the potential mechanism. Utilizing a network medicine approach, we efficaciously identified astragaloside IV (AsIV) and formononetin (FMT) as potential cardioprotective agents from 129 AR components. In vitro experiments on H9c2 rat cardiomyocytes demonstrated that the AsIV-FMT combination (AFC) significantly reduced doxorubicin-induced cell death in a dose-dependent manner, with an optimal ratio of 1:2. In vivo, AFC enhanced survival rates and improved cardiac function in both acute and chronic DIC mouse models. Further, AFC prevented cardiac injury and maintained the anticancer efficacy of doxorubicin in a breast cancer mouse model. Lipidomic and metabolomics analyses showed that AFC corrected doxorubicin-induced lipid profile abnormalities, particularly by reducing fatty acid accumulation. By gene knockdown and addition of inhibitor in H9C2 cells, we further found that PGC-1α and PPARα, two proteins related to fatty acid metabolism, were upregulated by AsIV and FMT, respectively. In summary, this study presents AFC as a promising therapy for DIC, emphasizing the importance of multi-target therapies derived from natural herbals in modern medicine.