Validated target-based network pharmacology reveals that salvianolic acid C attenuates doxorubicin-induced cardiotoxicity by regulating apoptosis and oxidative stress

Abstract

Doxorubicin (DOX), an anthracycline commonly used to treat various cancers, is associated with irreversible and dose-dependent cardiotoxicity. Salvianolic acid C (SAC) is a major polyphenolic compound in Salvia miltiorrhiza, an herbal medicine with significant cardioprotective effects. However, the role and mechanism of SAC in protecting against DIC remain unreported. Therefore, this study aims to investigate the protective effects and mechanisms of action of SAC against DOX-induced cardiotoxicity (DIC) through validated target-based network pharmacology. In vitro experiments using H9c2 cells revealed that SAC attenuated DOX-induced cardiomyocyte injury. Network pharmacology analysis revealed that apoptosis and oxidative stress play vital roles in mediating the protective effects of SAC against DIC. TUNEL staining and flow cytometry revealed that SAC inhibited DOX-induced apoptosis. Additionally, SAC mitigated DOX-induced oxidative stress by regulating the levels of reactive oxygen species, malondialdehyde, superoxide dismutase, and glutathione. Western blotting analysis revealed that SAC inhibited DOX-induced oxidative stress by reducing JNK phosphorylation, enhancing PI3K-AKT-mTOR pathway activation, and upregulating the antioxidant factors Nrf2 and HO-1. Furthermore, the reduction in cleaved caspase-3 and the increase in the Bcl-2/Bax ratio confirmed the inhibitory effect of SAC on apoptosis. Together, based on validated targets, these findings provide the first elucidation that SAC attenuates DIC by inhibiting apoptosis and oxidative stress through the regulation of the PI3K-AKT/JNK pathway, highlighting its potential for subsequent cotreatment with DOX in clinical applications.

Keywords: Apoptosis; Cardiotoxicity; Doxorubicin; Oxidative stress; Salvianolic acid C.