Abstract
Purpose: Doxorubicin (Dox) is a widely used anthracycline antibiotic with dose-dependent cardiotoxicity. Cardiac myocytes are highly energy-demanding cells that harbour a dense and well-structured mitochondrial network, which facilitates the accumulation of reactive Dox metabolites, causing disturbance of the mitophagy/biogenesis balance. We investigated the potential cardioprotective properties of liraglutide, a GLP-1 receptor agonist, either alone or in combination with pravastatin, in Dox-induced cardiotoxicity (DIC). Methods: Thirty-five male Sprague-Dawley rats were allocated into five groups (n= 7/group): normal control, doxorubicin, pravastatin & doxorubicin, liraglutide & doxorubicin, and pravastatin-liraglutide & doxorubicin groups. Cardiac histopathological assessment, as well as, echocardiography was performed at the end of the experiment to asses cardiac function along with measurement of CK-MB and troponin-T levels using ELISA. PINK1, Parkin, and PGC-1α gene expression levels were quantified using qRT-PCR while oxidative stress markers were analyzed biochemically. Results: Our findings demonstrated significant improvement in cardiac function, evidenced by the reduction in serum levels of cardiac injury markers, CK-MB and troponin-T, and restoration of mitophagy/biogenesis balance. This was supported by increased expression of PINK1, Parkin, and PGC-1α. Furthermore, co-administration of both drugs enhanced myocardial antioxidant capacity and reduced mitochondrial lipid peroxidation levels. Echocardiographic imaging and histopathological evaluations revealed preserved cardiac architecture and improved ventricular performance and fractional shortening, particularly in the combination therapy group. Conclusion: The enhanced effects highlight the therapeutic promise of combining pravastatin with liraglutide to counteract DIC, restoring mitochondrial dynamics, and strengthening antioxidant activity. Such modification of chemotherapeutic regimens may help safeguard cardiac health, improve quality of life, and reduce treatment-related complications.