FGF21/sirtuin 1 axis mediates the cardioprotective effects of high-intensity interval training against doxorubicin-induced cardiotoxicity by reducing inflammatory and oxidative stress

Doxorubicin (DOX) is a potent anthracycline chemotherapeutic agent, but its clinical use is limited by cumulative cardiotoxicity. Exercise, particularly high-intensity interval training (HIIT), has emerged as an effective non-pharmacological strategy to counteract chemotherapy-induced cardiac injury. However, the molecular mechanisms underlying the cardioprotective effects of HIIT remain unclear. This study aimed to determine whether HIIT attenuates DOX-induced cardiotoxicity via activation of the fibroblast growth factor 21 (FGF21)/sirtuin 1 (SIRT1) signalling pathway in rats. Thirty-three male Wistar rats (200-250 g) were randomly assigned to three groups (n = 11 each): control (CONTROL), DOX-treated sedentary (DOX-Sed) and DOX-treated HIIT (DOX-HIIT). DOX-induced cardiotoxicity was induced by intraperitoneal DOX injections (12 mg/kg cumulative dose over 12 days). After confirmation of cardiac dysfunction by echocardiography, the DOX-HIIT group completed an 8 week treadmill HIIT programme (three sessions per week, five intervals of 4 min at 85%-90% of maximal O₂ uptake separated by 2 min at 50%-60% of maximal O₂ uptake). Cardiac function, oxidative stress markers, inflammatory cytokines, plasma levels of FGF21 and protein expression of FGFR1 and the SIRT1/AMPK/Nrf2 pathway were assessed. HIIT improved survival (81.8% vs. 63.6% in DOX-Sed), prevented weight loss and ameliorated left ventricular systolic dysfunction, as evidenced by increased ejection fraction and fractional shortening (P < 0.05). HIIT reduced cardiac interleukin-6, tumor necrosis factor-α, interleukin-1β and malondialdehyde levels while elevating antioxidant enzyme activities. Mechanistically, HIIT increased plasma FGF21 and phosphorylated FGFR1 and upregulated SIRT1, LKB1 and phosphorylated AMPK, leading to activation of the Nrf2/HO-1 antioxidant pathway. Therefore, HIIT-induced FGF21 has a potential therapeutic effect on cardiac function in DOX-induced cardiotoxicity through activation of the FGF21/SIRT1/LKB1/AMPK/Nrf2/HO-1 signalling pathway.