Ferulic acid inhibits lipogenesis and ameliorates MASLD via targeting PGC-1β.

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic steatosis and increased triglyceride content. Thus, intervention in fatty acid metabolism is very desirable for NAFLD treatment. Ferulic acid (FA) is a plant-derived bioactive molecule that regulates lipid metabolism. Methods: High-fat diet (HFD)-fed mice and free fatty acid (FFA) -treated cells were used to evaluate the improvement of FA. The target proteins of FA were screened by solid phase extraction combined with mass spectrometry. Results: It was found that FA effectively improved MASLD in vivo and in vitro. Interestingly, PPAR gamma-coactivator-1beta (Ppargc1β, also known as PGC-1β) was the target of FA intervention in MASLD. FA directly bound to PGC-1β and inhibited its expression through the ubiquitin-proteasome pathway. Furthermore, Overexpression of PGC-1β abolished the ameliorative effect of FA on MASLD. In addition, FA inhibited lipogenesis through the PGC-1β/SREBP1 axis, thereby improving MASLD. Discussion: This work uncovered a novel plant-derived therapeutic strategy targeting a previously unrecognized PGC-1β/SREBP1 mechanism in MASLD.