Distinct Inhibitory Effects of Statin Lactones on Ca2+- and Na+/K+-ATPases

P-type ATPases share a conserved catalytic architecture but have different sensitivities to small-molecule inhibitors. We previously identified several statins as inhibitors of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), but the extent to which this inhibitory activity reflects broader pharmacological cross-reactivity among P-type ATPases remains unknown. Here, we compared the effects of seven structurally diverse statin lactones, which share a common δ-lactone moiety but contain distinct core scaffolds, including hexahydronaphthalene-based and aromatic heterocyclic ring systems, on SERCA and the Na+/K+-ATPase (NKA). The structurally related lovastatin and simvastatin produced similar concentration-dependent inhibitory profiles toward SERCA and NKA, despite the otherwise distinct pharmacological sensitivities of these pumps. In contrast, atorvastatin, rosuvastatin, and pitavastatin showed more divergent inhibitory profiles, generally with greater inhibition of SERCA than NKA at higher concentrations. Pravastatin and fluvastatin, however, had minimal effects on either ATPase over the concentration range examined. These findings build on our previous identification of selected statins as SERCA inhibitors by demonstrating that their activity can extend to NKA. Overall, the results reveal substantial structure-dependent variation in the effects of statin lactones on these P-type ATPases, ranging from convergent inhibition to differential inhibition and minimal activity.