Preventive Aerobic Training Protects Against Doxorubicin-Induced Cardiotoxicity by Preserving Redox Status and Attenuating Cardiac Stress-Related Signaling

Doxorubicin (DOX) is a highly effective chemotherapeutic agent whose clinical use is limited by dose-dependent cardiotoxicity associated with oxidative stress, inflammation, and cellular stress responses. Here, we investigated whether preventive aerobic training could protect against DOX-induced cardiac injury in Wistar rats. Animals were assigned to sedentary control (C), sedentary DOX (D), trained control (CT), and trained DOX (DT) groups. The moderate-intensity (~50-80% maximal exercise test) treadmill protocol (40 min/day, 4 days/week for 4 weeks) was performed before intraperitoneal administration of DOX (4 mg/kg, weekly for 4 weeks) or saline. Preventive training markedly improved exercise capacity (<i>p</i> < 0.001) and attenuated oxidative damage, maintaining antioxidant enzyme activity (GR, SOD) at control levels (<i>p</i> > 0.05). DOX significantly upregulated cardiac <i>IL-6</i> and <i>IL-1β</i> expression (<i>p</i> < 0.01), while trained animals preserved <i>IL-1β</i> expression similar to controls (<i>p</i> > 0.99). In parallel, DOX increased cardiac <i>HIF-1</i> expression (<i>p</i> < 0.05), indicating activation of hypoxia- and stress-related signaling pathways, an effect that was attenuated by preventive training (<i>p</i> > 0.99). DOX-induced cardiac atrophy was evidenced by reduced left ventricular mass (<i>p</i> < 0.001), which was partially prevented by training (<i>p</i> < 0.05). Although hematological toxicity persisted, preventive aerobic exercise effectively counteracted DOX cardiotoxicity by restoring redox homeostasis, dampening inflammation, and limiting apoptotic signaling. Collectively, these findings highlight exercise preconditioning as a promising non-pharmacological strategy in cardio-oncology to mitigate chemotherapy-associated cardiac injury.