Background <p>Sunitinib is an orally administered novel multi-targeted therapy for treating tumors especially for gastrointestinal stromal tumors and metastatic renal cell carcinoma (RCC) but associated with cardiovascular toxicity. Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that not only improves heart failure caused by various factors but also plays a role in mediating apoptosis in tumor cells. However, the role of dapagliflozin in sunitinib-induced cardiotoxicity remains unclear.</p> Methods <p>Immunodeficient mice were subcutaneously injected with RCC cells to establish a xenograft tumor model, and were treated with sunitinib and dapagliflozin to explore the impact of dapagliflozin on the antitumor effects of sunitinib and its cardiac toxicity. Additionally, C57BL/6 mice were administrated with sunitinib to study its cardiac toxicity on normal mice. Finally, RNA-seq analysis was utilized to elucidate the specific mechanisms by which dapagliflozin mitigates sunitinib-induced cardiac toxicity.</p> Results <p>Dapagliflozin attenuates sunitinib-induced cardiotoxicity while potentiating the antitumor efficacy of sunitinib. In addition to causing cardiomyocyte apoptosis and oxidative stress, sunitinib worsens cardiac function and affects electron transport chain (ETC) activity, leading to reduced cardiac energy supply and disrupting fatty acid metabolism. Fortunately, dapagliflozin can rescue ETC activity, promote fatty acid metabolism, reduce cardiac oxidative stress levels, and ultimately prevent cardiac dysfunction. Mechanistically, dapagliflozin exerts a protective effect against sunitinib-induced cardiac toxicity by activating PPARα through an AMPKα-dependent pathway.</p> Conclusions <p>Our results demonstrate that dapagliflozin not only enhances the antitumor efficacy of sunitinib against renal cell carcinoma but also alleviates sunitinib-induced cardiac toxicity in mice via modulation of the AMPKα-PPARα axis.</p> Graphical Abstract <p></p>