Artesunate ameliorates doxorubicin-induced cardiotoxicity by promoting HuR binding to Sirt1 mRNA

Doxorubicin (DOX), a widely used chemotherapeutic agent for malignancies, exhibits dose-dependent cardiotoxicity, which restricts its clinical utility. While artesunate (ART) demonstrates potentially cardioprotective effects against acute DOX-induced cardiac damage, its role in chronic cardiotoxicity and its underlying mechanisms remain unclear. This study aimed to elucidate the mechanism underlying artesunate-mediated protection against doxorubicin (DOX)-induced cardiotoxicity.

Mice were treated with 5 mg/kg DOX (intraperitoneal injection) once weekly for 4 weeks to induce myocardial damage and with 25 mg/kg ART (intragastric administration) for 28 days. Echocardiography and histological staining were used to evaluate cardiac function and structural changes. We also assessed mRNA and protein levels using real-time polymerase chain reaction and Western blotting, respectively, and evaluated HuR-Sirt1 mRNA interaction via RNA immunoprecipitation (RIP).

ART treatment significantly ameliorated DOX-induced cardiac dysfunction, fibrosis, hypertrophy, and apoptosis both in vivo and in vitro. Furthermore, ART restored cardiac sirtuin-1 (Sirt1) expression, which was suppressed by DOX. Critically, cardiac-specific Sirt1 knockout exacerbated DOX-induced cardiac damage and abolished the protective effects of ART. Mechanistically, we observed that siRNA-mediated HuR knockdown reduced Sirt1 expression, whereas Sirt1 knockdown did not affect HuR expression, indicating that HuR positively regulates Sirt1 expression. ART promotes the nuclear-to-cytoplasmic translocation of HuR, thereby enhancing its binding to Sirt1 mRNA and stabilizing Sirt1 transcripts.

Collectively, these findings demonstrate that ART attenuates DOX cardiotoxicity by activating the HuR-Sirt1 axis through the stabilization of Sirt1 mRNA.