SKLB023 as an iNOS inhibitor alleviated liver fibrosis by inhibiting the TGF-beta/Smad signaling pathway

Nonalcoholic steatohepatitis (NASH)-related liver fibrosis has been suggested to be a physiological consequence of chronic hepatic injury, necrosis, inflammation and unbalanced intrahepatic lipid metabolism. Accumulated evidence demonstrates that inducible nitric oxide synthase (iNOS) is highly expressed in advanced liver fibrosis, and the knockout of iNOS inhibits the progression of hepatic fibrosis. In our previous study, (Z)-N-(3-chlorophenyl)-2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)acetamide (SKLB023), a novel small-molecule inhibitor of iNOS, blocked joint inflammation and cartilage destruction in arthritis. However, the role and function of SKLB023 in liver fibrosis have not been fully elucidated. In the present study, methionine- and choline-deficient (MCD) diet-induced NASH mice and LX-2 hepatic stellate cells were chosen to investigate the pharmacological effects of SKLB023 against liver fibrosis and the associated mechanism. Our results show that SKLB023 significantly alleviated MCD diet-induced liver injury, lipid accumulation and liver fibrosis. SKLB023 could suppress the activation of hepatic stellate cells by interfering with TGF-/Smad pathways. Importantly, SKLB023 inhibited the level of TGF-1 and Smad2/3 phosphorylation by blocking the expression of iNOS. These results suggest that SKLB023 might be an effective drug candidate for the treatment of liver fibrosis.