Abstract

Dapagliflozin (DAPA) is the first sodium-glucose cotransporter 2 (SGLT2) inhibitor to receive approval for clinical use in China. However, the mechanism behind the cardioprotective effects of DAPA remains unclear, as cardiac tissue does not express SGLT2. This study investigated the efficacy of DAPA in alleviating myocardial ischemia-reperfusion (MIR) injury, independent of its glucose-lowering properties. The findings revealed that DAPA significantly improved cardiac function and decreased ventricular remodeling in a murine model of MIR injury-induced heart failure (HF). Furthermore, bioinformatics and cellular thermal shift assays (CETSAs) revealed that retinoid-related orphan receptor gamma t (RORγt) acts as a specific molecular target. Moreover, DAPA alleviated MIR injury-induced increased cardiac CD4 + T cells as well as RORγt, interleukin-17 A (IL-17 A), and CD4 levels in cardiac tissue. This immunomodulatory effect was clinically significant, as proportions of peripheral blood T helper 17 (Th17) cells were significantly decreased in post-acute myocardial infarction (post-AMI) HF patients undergoing DAPA therapy. In conclusion, the study investigated the cardioprotective effects of DAPA, demonstrating that it can modulate the cardiac immune micro-environment via RORγt, which regulates the CD4 + T cell/Th17 cell axis within cardiac tissue. These findings offer mechanistic validation for the tissue-specific therapeutic effects of DAPA in the heart, establishing pharmacological regulation of immune metabolic pathways as an innovative precision medicine strategy for HF, and highlighting its translational potential.