Abstact

Bempedoic acid (BA) is a recently approved drug that lowers cholesterol and hepatic lipids, yet its mechanism of action remains incompletely understood. Here, we combine transcriptomic, biochemical, and structural approaches to show that BA directly binds to and activates peroxisome proliferator-activated receptor alpha (PPARalpha). BA treatment robustly induced PPARalpha signaling and fatty acid oxidation in primary hepatocytes and mouse liver. Through X-ray crystallography, we uncovered that BA binds to the ligand-binding domain of PPARalpha and stabilizes its active conformation. BA activated PPARalpha target genes independently of very-long-chain acyl-coenzyme A (CoA) synthetase (ACSVL1), the liver-enriched enzyme that converts BA to its bempedoyl-CoA form. Notably, BA-mediated induction of fatty acid oxidation required PPARalpha. Together, this work reveals direct PPARalpha activation as a key mechanism of BA action, providing a molecular basis for its lipid-lowering effects and suggesting broader therapeutic potential beyond the liver.