Ursolic acid ameliorates doxorubicin-induced cardiotoxicity by inhibiting DRP1-mediated excessive mitochondrial fission and oxidative stress

Background: Doxorubicin (DOX) is a commonly used chemotherapeutic agent for treating hematologic malignancies and breast Cancer. However, its clinical application is limited by severe cardiotoxicity. Recent studies have suggested that mitochondrial dynamics play a central role in the pathogenesis of doxorubicin-induced cardiotoxicity (DIC). This study was designed to evaluate whether ursolic acid (UA) can mitigate DIC and elucidate the underlying mechanisms related to mitochondrial fission and oxidative stress.

Methods: A chronic DOX-induced cardiotoxicity model was established via the intraperitoneal administration of DOX (5 mg/kg/week), while ursolic acid was administered intragastrically (50 mg/kg/day). Echocardiography and histological staining were employed to assess the protective effects of ursolic acid on DOX-induced cardiac injury.

Results: Ursolic acid treatment significantly improved cardiac function following DOX exposure. Immunofluorescence analysis confirmed the amelioration of mitochondrial dysfunction. Western blotting demonstrated that ursolic acid markedly reduced the DOX-induced increase in the level of dynamin-related protein 1 (DRP1) phosphorylated at Ser616 (p-DRP1(S616)), suggesting its role in attenuating excessive mitochondrial fission. Furthermore, co-treatment with Mitochondrial Division Inhibitor 1 (Mdivi-1) further suppressed p-DRP1 (S616) expression, reinforcing the notion that ursolic acid mitigates DIC by inhibiting DRP1-mediated mitochondrial fission and oxidative stress. The upstream mechanism was explored, with evidence suggesting that the C5a-C5a1 receptor axis mediates p-DRP1(S616) phosphorylation. Western blot analysis revealed significant upregulation of the C5a and C5a1 receptors in the DIC model. The C5a1 receptor agonist BM213 abolished the protective effects of ursolic acid, indicating that ursolic acid exerts its cardioprotective effect by inhibiting the C5a-C5aR1-DRP1(S616) pathway.

Conclusion: Ursolic acid confers protection against DOX-induced cardiotoxicity by improving mitochondrial function through the inhibition of DRP1-mediated excessive mitochondrial fission and oxidative stress.

Doxorubicin-induced cardiotoxicity; Mitochondrial fission; Oxidative stress; Ursolic acid; p-DRP1(S616).