Imidazole-Based ALK5 Inhibitor Attenuates TGF-β/Smad-Mediated Hepatic Stellate Cell Activation and Hepatic Fibrogenesis.

Abstract

Liver fibrosis resulting from severe liver damage is a major clinical problem for which effective pharmacological drugs and treatment strategies are lacking. TGF-β, a hallmark of liver fibrosis, has been shown to promote ALK5 phosphorylation in an activated state. Hence, the suppression of ALK5 signal transduction has emerged as a promising therapeutic strategy for the treatment of liver fibrosis. In this study, the imidazole derivative J-1149, which exhibited inhibitory activity against ALK5, was synthesized to exert antifibrotic effects, and the inhibition mechanisms were uncovered. Our findings suggested that J-1149 significantly attenuated HSC activation and liver fibrogenesis by acting on the TGF-β/Smad signaling pathway. Concurrently, the potential of J-1149 to impede the P2X7R/NLRP3 axis, curtail the infiltration of macrophages and neutrophils, and reduce liver fibrogenesis was also highlighted. These results demonstrated that J-1149 is a promising candidate for the treatment of liver fibrosis.