TY  - JOUR
AU  - Papa, Christina
AU  - Rose, Alina
AU  - Martin, Hugo N. G.
AU  - Useini, Abibe
AU  - Geier, Florian
AU  - Liao, Longsheng
AU  - Rodríguez-Aguilera, Jesús Rafael
AU  - Valina-Allo, Philipp
AU  - Hoffmann, Anne
AU  - Tvardovskiy, Andrey
AU  - Zulfqar, Faiqa
AU  - Zimmerman, Andrea
AU  - Schicht, Gerda
AU  - Ott, Fritzi
AU  - Körner, Christiane
AU  - Engelmann, Beatrice
AU  - Rolle-Kampczyk, Ulrike
AU  - von Bergen, Martin
AU  - Meier, Matthias
AU  - Bartke, Till
AU  - Seehofer, Daniel
AU  - Klöting, Nora
AU  - Matz-Soja, Madlen
AU  - Damm, Georg
AU  - Boeckel, Jes-Niels
AU  - Buescher, Joerg M.
AU  - Blüher, Matthias
AU  - Laufs, Ulrich
AU  - Bondareva, Olga
AU  - Sträter, Norbert
AU  - Künze, Georg
AU  - Heiker, John T.
AU  - Sheikh, Bilal N.
TI  - Bempedoic acid directly binds and activates PPARα
JO  - Cell metabolism
VL  - xx
SN  - 1550-4131
CY  - Amsterdam [u.a.]
PB  - Elsevier
M1  - PUBDB-2026-00792
SP  - S1550413125005492
PY  - 2026
AB  - 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 (PPARα). BA treatment robustly induced PPARα 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 PPARα and stabilizes its active conformation. BA activated PPARα 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 PPARα. Together, this work reveals direct PPARα 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.
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1016/j.cmet.2025.12.018
UR  - https://bib-pubdb1.desy.de/record/646269
ER  -