SGLT2 inhibitors activate pantothenate kinase in the human heart

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce mortality in heart failure, but their pharmacological target remains unclear. In this study, we showed that SGLT2i directly activate pantothenate kinase 1 (PANK1), the rate-limiting enzyme in coenzyme A (CoA) synthesis. Using stable isotope infusions, we established that SGLT2i activate CoA synthesis and broadly stimulate fuel use in human cardiac tissue. We also demonstrated that SGLT2i bind PANK1 at physiological concentrations, directly inducing conformational changes and increasing enzymatic activity. In silico modeling identified the site of SGLT2i binding on PANK1, which was confirmed by amino acid mutagenesis. Finally, we showed that SGLT2i-mediated PANK activation is necessary and sufficient to increase contractility of human cardiomyocytes. In summary, we demonstrate off-target activation of PANK1 and promotion of CoA synthesis by SGLT2i, which may explain their marked clinical benefits.