Design and synthesis of novel ATP-citrate lyase inhibitors and their effects on MAFLD/MASH.

ATP-citrate lyase (ACLY) has emerged as a promising therapeutic target for metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatohepatitis (MASH). Inspired by the common pharmacophore of natural ACLY inhibitors, we designed and synthesized a novel series of chalcone-skeleton derivatives. Extensive structure-activity relationship (SAR) studies revealed that introducing conformational constraint, particularly through five-membered ring formation (e.g., compound B1) or a rigid benzofuran scaffold (e.g., compound C1), remarkably enhanced ACLY inhibition. This optimization culminated in the discovery of C1, which demonstrated potent activity with an IC50 value of 0.022 μM. Mechanism of action studies suggested that both B1 and C1 interacted with the allosteric binding site of ACLY. Furthermore, these lead compounds exhibited excellent lipid-lowering efficacy in vitro and in vivo. In a high-fat diet-induced murine model of MASH, administering B1 and C1 significantly alleviated hepatic steatosis, systemic insulin resistance, and oxidative stress. Notably, they also ameliorated key pathological drivers of disease progression, including liver inflammation and fibrosis. Collectively, our findings identify B1 and C1 as novel and highly effective ACLY inhibitors and hold significant therapeutic potential for MAFLD/MASH.