Targeting acetyl-CoA carboxylases for the treatment of MASLD.

Hepatic accumulation of triglycerides is a hallmark feature of metabolic dysfunction-associated steatotic liver disease (MASLD). Growing evidence indicates that increased rates of de novo lipogenesis (DNL) are one of the earliest metabolic changes promoting hepatic steatosis in the onset of MASLD. The first step in DNL is catalyzed by acetyl-CoA carboxylases (ACC), which mediate the conversion of acetyl-CoA into malonyl-CoA. Given the critical role of ACC enzymes on DNL, ACC-based therapies have emerged as an attractive approach to address MASLD, leading to the development of pharmacologic inhibitors of ACC. In clinical trials, several of those compounds led to decreased DNL rates and improved hepatic steatosis in patients with MASLD. In this review, we describe the development of ACC dual inhibitors and isoform-specific inhibitors along with their clinical testing using monotherapy and combination therapy approaches. We also discuss their efficacy and safety profiles, identifying potential directions for future research. It is anticipated that advances in ACC-based therapies will be critical to the management of MASLD.