Hydronidone ameliorates liver fibrosis by inhibiting activation of hepatic stellate cells via Smad7‐mediated degradation of TGFβRI

• DOI: 10.1111/liv.15715
• Publication Date: 2023-08-29T06:31:36Z
• Authors: Xianjun Xu; Yuecheng Guo; Xin Luo; Zhenyang Shen; Zhongshang Sun; Bo Shen; Cui Zhou; Junjun Wang; Jingyi Lu; Qingqing Zhang; Yanping Ye; Ying Luo; Ying Qu; Xiaobo Cai; Hui Dong; Lungen Lu
• Keywords: Liver Cirrhosis; Mice; Liver; Transforming Growth Factor beta; Hepatic Stellate Cells; Receptor, Transforming Growth Factor-beta Type I; Animals; Carbon Tetrachloride; 3. Good health; Signal Transduction; Smad7 Protein

AbstractBackground and PurposeLiver 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.MethodsThe 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.ResultsIn 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 β receptor I (TGFβRI) in HSCs and thus inhibited the TGFβ‐Smad signalling pathway. Specific knockdown of Smad7 in HSCs in vivo blocked the antifibrotic effect of hydronidone.ConclusionHydronidone ameliorates liver fibrosis by inhibiting HSCs activation via Smad7‐mediated TGFβRI degradation. Hydronidone is a potential drug candidate for the treatment of liver fibrosis.