Sacubitril valsartan combined with bisoprolol reduces doxorubicin-induced cardiotoxicity in rats by attenuating oxidative stress

Doxorubicin-induced cardiotoxicity remains a leading cause of mortality among cancer patients, with oxidative stress serving as a central pathogenic mechanism. This study investigated whether combination therapy with sacubitril valsartan and bisoprolol attenuates doxorubicin-induced cardiotoxicity through modulation of oxidative stress pathways. Sixty male Sprague-Dawley rats were randomized into five groups: control, doxorubicin (DOX), bisoprolol (1.0 mg/kg/d), sacubitril valsartan (30 mg/kg/d), and combination therapy. All groups except control received intraperitoneal DOX (2.5 mg/kg weekly for 5 weeks). Cardiac function was assessed by echocardiography, myocardial injury by histopathology and enzyme levels (CK-MB, cTnI, BNP), and oxidative stress by ROS fluorescence, MDA, and SOD. Protein expression of Nrf2, HO-1, and Keap1 was analyzed by Western blot. DOX administration significantly impaired cardiac function, induced myocardial structural damage, elevated cardiac enzymes and oxidative stress markers, and downregulated Nrf2 pathway proteins compared to controls (all P < 0.05). All treatment groups significantly attenuated these abnormalities versus DOX (all P < 0.05), with combination therapy demonstrating superior cardioprotection evidenced by greatest improvement in LVEF (68.74 ± 6.87% vs. 50.26 ± 6.11%, P < 0.05), lowest cardiac enzyme levels, and most robust restoration of Nrf2 pathway expression. These findings demonstrate that sacubitril valsartan combined with bisoprolol effectively reduces doxorubicin-induced cardiotoxicity in rats by activating Nrf2-mediated antioxidant responses, providing experimental evidence for a potentially synergistic prophylactic strategy.