Biochemical reassessment of the activation of PANK1 by SGLT2 inhibitors

Although SGLT2 inhibitors (SGLT2i) show cardiovascular benefits in addition to glycemic control, their molecular target for cardiovascular effect remains unclear. A recent study reported that two SGLT2i, empagliflozin and dapagliflozin, directly activate pantothenate kinase 1 (PANK1), which mediate their cardioprotective effect. PANK1 phosphorylates pantothenate with ATP to yield 4'-phosphopantothenate and ADP, representing the rate-limiting enzyme of coenzyme A (CoA) biosynthesis. We therefore reassessed this claim using purified recombinant human PANK1. The malachite green assay detected free inorganic phosphate (Pi) but neither ADP nor 4'-phosphopantothenate and its signals do not reflect PANK1 activity. In the ADP-Glo assay, empagliflozin and dapagliflozin did not stimulate PANK1 under either basal conditions or acetyl-CoA feedback inhibition, while the activator PZ-2891 enhanced the activity of PANK1. These results show that SGLT2i do not directly activate PANK1, challenging the proposed PANK1-dependent cardioprotection mechanism.