HYDRONIDONE AMELIORATES LIVER FIBROSIS BY INHIBITING ACTIVATION OF HEPATIC STELLATE CELLS VIA Smad7-MEDIATED DEGRADATION OF TGF.RI

Background and Purpose: Liver fibrosis is a wound-healing reaction that eventually leads to cirrhosis. Hydronidone is a new pyridine derivative with the potential to treat liver fibrosis. In this study, we explored the antifibrotic effects of hydronidone and its potential mode of action.Methods: The anti-hepatic fibrosis effects of hydronidone were studied in carbon tetrachloride (CCl4)- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- induced animal liver fibrosis. The antifibrotic mechanisms of hydronidone were investigated in hepatic stellate cells (HSCs). The antifibrotic effect of hydronidone was further tested after Smad7 knockdown in HSCs in mouse models of fibrosis.Results: In animal models, hydronidone attenuated liver damage and collagen accumulation, and reduced the expression of fibrosis-related genes. Hydronidone decreased the expression of fibrotic genes in HSCs. Impressively, hydronidone significantly upregulated Smad7 expression and promoted the degradation of transforming growth factor beta receptor I (TGF beta RI) in HSCs and thus inhibited the TGF beta-Smad signalling pathway. Specific knockdown of Smad7 in HSCs in vivo blocked the antifibrotic effect of hydronidone.Conclusion: Hydronidone ameliorates liver fibrosis by inhibiting HSCs activation via Smad7-mediated TGF beta RI degradation. Hydronidone is a potential drug candidate for the treatment of liver fibrosis.