Efonidipine inhibiting CYP4A attenuates palmitate-induced hepatocyte lipotoxicity.

Efonidipine, a dual L-/T-type calcium channel blocker (CCB), is a clinically established antihypertensive agent with cardiovascular and renoprotective effects. However, whether efonidipine affects CYP4A, a previously established mediator of hepatic lipotoxicity, remains unknown. In the present study, palmitate (PA)-induced steatotic HepG2 and SNU-449 hepatocytes were used to evaluate the hepatoprotective effects of efonidipine and its underlying mechanism. Efonidipine inhibited CYP4A enzyme activity, revealing a previously unrecognized CYP4A inhibitor. It also reduced CYP4A protein expression in PA-treated hepatocytes. This was accompanied by reduced intracellular lipid accumulation and lipogenesis, suppressed oxidative and ER stress, and improved insulin signaling and glucose uptake. These effects were consistently observed in both hepatocyte cell lines. Taken together, these findings suggest that efonidipine may represent a potential repurposing strategy for hepatic lipotoxicity through CYP4A inhibition.