SIRT4 Suppresses Doxorubicin-Induced Cardiotoxicity by Regulating the AKT/mTOR/Autophagy Pathway

Doxorubicin (DOX) is a potent anthracycline chemotherapeutic drug. DOX-induced cardiotoxicity (DIC) limits its application in cancer treatment, as this complication is detrimental and fatal. Reactive oxygen species (ROS) production, autophagic dysfunction and cell death are crucial factors related to DIC. Previous studies have shown that SIRT4 is associated with cardiac energy metabolism, cardiac mitochondrial dysfunction and cardiac cell death, but it is unclear whether SIRT4 affects DOX-induced cardiac injury. Our data suggested that SIRT4 overexpression in vivo and in vitro could alleviate DIC by improving cardiac function and reducing cardiomyocyte apoptosis and autophagy. However, autophagy activation by rapamycin abolished the protective effect of SIRT4 overexpression on DIC. Furthermore, in the context of DOX treatment, SIRT4 overexpression activated the Akt/mTOR signaling pathway and inhibited autophagy through the Akt/mTOR signaling pathway. Our findings indicate that SIRT4 overexpression protects against DIC by inhibiting Akt/mTOR-dependent autophagy. These findings may provide a prospective therapeutic target for DIC.