Exercise improves doxorubicin-induced cardiotoxicity by regulating mitochondrial quality control through activation of the SIRT1-FOXO1 pathway

Doxorubicin (DOX) is a highly effective broad-spectrum chemotherapeutic agent, yet its clinical application is severely limited by dose-dependent cardiotoxicity, for which preventive strategies are lacking. Exercise has emerged as a promising non-pharmacological intervention; its cardioprotective effects may involve silent information regulator 1 (SIRT1), though the precise mechanisms remain unclear. This study aimed to investigate the effect of exercise intensity on DOX-induced cardiotoxicity through the SIRT1-FOXO1 pathway and mitochondrial homeostasis. Using a murine model of DOX-induced cardiac injury, we implemented exercise regimens of varying intensities. Results demonstrated that moderate-intensity exercise (MIE) significantly attenuated DOX-induced cardiac dysfunction, apoptosis, and oxidative stress, while favorably regulating proteins essential for mitochondrial biogenesis and dynamics.Mechanistically, MIE activated myocardial SIRT1, leading to deacetylation of FOXO1, which enhanced antioxidant defenses and conferred cardioprotection. Notably, low-intensity exercise (LIE) offered only modest benefits, whereas high-intensity exercise (HIE) exacerbated myocardial oxidative stress and injury.Collectively, our findings establish that MIE alleviates DOX-induced cardiotoxicity by activating the SIRT1-FOXO1 pathway and restoring mitochondrial homeostasis, thereby providing a critical experimental foundation for developing tailored exercise regimens to prevent chemotherapy-related cardiac dysfunction..