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

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

doi:10.1111/liv.15715

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

Liver Int. 2023 Nov;43(11):2523-2537. doi: 10.1111/liv.15715. Epub 2023 Aug 28.

Authors

Xianjun Xu^{1

2}, Yuecheng Guo^{1

2}, Xin Luo^{1

2}, Zhenyang Shen^{1

2}, Zhongshang Sun³, Bo Shen^{1

2}, Cui Zhou^{1

2}, Junjun Wang^{1

2}, Jingyi Lu^{1

2}, Qingqing Zhang^{1

2}, Yanping Ye⁴, Ying Luo⁴, Ying Qu^{1

2}, Xiaobo Cai^{1

2}, Hui Dong^{1

2}, Lungen Lu^{1

2}

Affiliations

¹ Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Gastroenterology, Huaian First People's Hospital, Nanjing Medical University, Huaian, China.
⁴ Continent Pharmaceuticals Co., Ltd., Beijing, China.

PMID: 37641479
DOI: 10.1111/liv.15715

Abstract

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 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.

Conclusion: Hydronidone ameliorates liver fibrosis by inhibiting HSCs activation via Smad7-mediated TGFβRI degradation. Hydronidone is a potential drug candidate for the treatment of liver fibrosis.

Keywords: HSCs; Smad7; TGFβRI; hydronidone; liver fibrosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carbon Tetrachloride / metabolism
Carbon Tetrachloride / toxicity
Hepatic Stellate Cells / drug effects
Hepatic Stellate Cells / metabolism
Liver / pathology
Liver Cirrhosis* / drug therapy
Mice
Receptor, Transforming Growth Factor-beta Type I
Signal Transduction*
Smad7 Protein / drug effects
Smad7 Protein / metabolism
Transforming Growth Factor beta* / metabolism

Substances

Carbon Tetrachloride
hydronidone
Receptor, Transforming Growth Factor-beta Type I
Transforming Growth Factor beta
Smad7 Protein