Fluorofenidone alleviates liver fibrosis by inhibiting hepatic stellate cell autophagy via the TGF-β1/Smad pathway: implications for liver cancer

Xiongqun Peng; Huixiang Yang; Lijian Tao; Jingni Xiao; Ya Zeng; Yueming Shen; Xueke Yu; Fei Zhu; Jiao Qin

doi:10.7717/peerj.16060

Fluorofenidone alleviates liver fibrosis by inhibiting hepatic stellate cell autophagy via the TGF-β1/Smad pathway: implications for liver cancer

PeerJ. 2023 Sep 28:11:e16060. doi: 10.7717/peerj.16060. eCollection 2023.

Authors

Xiongqun Peng¹, Huixiang Yang², Lijian Tao³, Jingni Xiao⁴, Ya Zeng¹, Yueming Shen¹, Xueke Yu¹, Fei Zhu⁵, Jiao Qin⁴

Affiliations

¹ Department of Gastroenterology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China.
² Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China.
³ Department of Nephropathy, Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Nephrology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China.
⁵ Department of General Surgery, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China.

Abstract

Objectives: Liver fibrosis is a key stage in the progression of various chronic liver diseases to cirrhosis and liver cancer, but at present, there is no effective treatment. This study investigated the therapeutic effect of the new antifibrotic drug fluorofenidone (AKF-PD) on liver fibrosis and its related mechanism, providing implications for liver cancer.

Materials and methods: The effects of AKF-PD on hepatic stellate cell (HSC) autophagy and extracellular matrix (ECM) expression were assessed in a carbon tetrachloride (CCl₄)-induced rat liver fibrosis model. In vitro, HSC-T6 cells were transfected with Smad2 and Smad3 overexpression plasmids and treated with AKF-PD. The viability and number of autophagosomes in HSC-T6 cells were examined. The protein expression levels of Beclin-1, LC3 and P62 were examined by Western blotting. The Cancer Genome Atlas (TCGA) database was used for comprehensively analyzing the prognostic values of SMAD2 and SMAD3 in liver cancer. The correlation between SMAD2, SMAD3, and autophagy-related scores in liver cancer was explored. The drug prediction of autophagy-related scores in liver cancer was explored.

Results: AKF-PD attenuated liver injury and ECM deposition in the CCl₄-induced liver fibrosis model. In vitro, the viability and number of autophagosomes in HSCs were reduced significantly by AKF-PD treatment. Meanwhile, the protein expression of FN, α-SMA, collagen III, Beclin-1 and LC3 was increased, and P62 was reduced by the overexpression of Smad2 and Smad3; however, AKF-PD reversed these effects. SMAD2 and SMAD3 were hazardous factors in liver cancer. SMAD2 and SMAD3 correlated with autophagy-related scores in liver cancer. Autophagy-related scores could predict drug response in liver cancer.

Conclusions: AKF-PD alleviates liver fibrosis by inhibiting HSC autophagy via the transforming growth factor (TGF)-β1/Smadpathway. Our study provided some implications about how liver fibrosis was connected with liver cancer by SMAD2/SMAD3 and autophagy.

Keywords: AKF-PD; Autophagy; Hepatic stellate cell; Liver fibrosis; TGF-β1/Smad pathway.

Publication types

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

MeSH terms

Animals
Autophagy
Beclin-1 / metabolism
Fibrosis
Hepatic Stellate Cells*
Liver Cirrhosis / drug therapy
Liver Neoplasms* / drug therapy
Rats
Signal Transduction
Transforming Growth Factor beta1 / genetics

Substances

Transforming Growth Factor beta1
5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone
Beclin-1

Grants and funding

This study was funded by the Changsha Municipal Natural Science Foundation (Grant No. kq2014021), the Scientific Research Project of Hunan Provincial Health Commission (Grant No. 202303037199 and 202203052625, the Hunan Provincial Natural Science Foundation—Youth Foundation (Grant No. 2020JJ5611), and the Changsha Central Hospital Subject (Grant Nos. YNKY 202139 and YNKY 202101). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.