Mitigating doxorubicin-induced hepatotoxicity in male rats: The role of aerobic interval training and curcumin supplementation in reducing oxidative stress, endoplasmic reticulum stress and apoptosis

Doxorubicin (DOXO) is a powerful anthracycline chemotherapeutic drug, but its clinical usage has been limited by its deleterious effects on different organs, particularly hepatotoxicity. The aim of this study was to establish the combined effects of aerobic interval training (AIT) and curcumin supplementation on mitigating oxidative damage and endoplasmic reticulum (ER) stress-mediated apoptosis in a rat model of DOXO-induced hepatotoxicity. Fifty-six male Sprague-Dawley rats were randomly split into six groups: control (CON), vehicle, doxorubicin (Dox), doxorubicin + curcumin (Dox-C), doxorubicin + AIT (Dox-A), and doxorubicin + curcumin + AIT (Dox-AC). DOXO was intraperitoneally injected weekly (4 mg/kg/week) for five weeks. Curcumin supplementation (100 mg/kg/day) and AIT (4 min at 80-90% of VO_2max intermitted by 3 min of active rest at 65-75% of VO_2max) were conducted five times a week for six weeks. Finally, the hepatic tissue and blood samples were collected to assess histopathological changes, liver damage biomarkers, and the protein expression of oxidative stress, ER stress, and apoptosis markers. Tissue sections revealed that AIT and curcumin supplementation significantly improved hepatotoxicity induced by DOXO, as evidenced by the positive effects on histopathological alterations and serum markers of hepatic damage (P < 0.05). Both curcumin and AIT significantly reduced DOXO-triggered oxidative damage, ER stress, and apoptosis (P < 0.05), with the latter showing slightly higher effectiveness. Consequently, the combination of AIT with curcumin supplementation exhibits protective effects against chronic hepatotoxicity induced by DOXO, with AIT demonstrating relatively greater efficacy in increasing antioxidant capacity and reducing ER stress and apoptosis.