To study the potential mechanism of the SGLT2 inhibition in heart failure, we used the murine doxorubicin-induced cardiomyopathy model and identified the toll-like receptor 9 (TLR9), NAD-dependent deacetylase sirtuin-3 (SIRT3), and Beclin 1, acting in a complex together in response to empagliflozin treatment. Here, SLC5A2 is linked to heart failure.