Abstract

Sorafenib is a first-line tyrosine kinase inhibitor for malignant tumor treatment, yet its clinical application is greatly restricted by unavoidable cardiotoxicity. Astragaloside IV is a natural compound with prominent cardiovascular protective effects. We first carried out modeling studies including network pharmacology, human proteome microarray screening, molecular docking, and molecular dynamics simulation. Network pharmacology highlighted the hypoxia-inducible factor-1 signaling pathway as a key route; the integrated approach further identified signal transducer and activator of transcription 3 as a novel direct binding target of astragaloside IV with high binding stability. In a mouse model of chronic sorafenib-induced cardiotoxicity, astragaloside IV significantly improved cardiac function, and attenuated myocardial fibrosis, oxidative damage, and cardiomyocyte apoptosis. Mechanistically, astragaloside IV reduced the expression of signal transducer and activator of transcription 3 and hypoxia-inducible transcription factor-1α, and elevated the expression of B-cell lymphoma 2. In cellular experiments, astragaloside IV protected HL-1 cardiomyocytes against sorafenib-induced cytotoxicity and apoptosis through the same signaling pathway. This study confirms that astragaloside IV alleviates sorafenib-induced cardiotoxicity by inhibiting cardiomyocyte apoptosis via targeting the signal transducer and activator of transcription 3/hypoxia-inducible transcription factor-1α/B-cell lymphoma 2 pathway, providing a promising strategy for clinical prevention of chemotherapy-related cardiac injury.