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

PeerJ (Sep 2023)

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

Affiliations

Xiongqun Peng: Department of Gastroenterology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
Huixiang Yang: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China
Lijian Tao: Department of Nephropathy, Xiangya Hospital, Central South University, Changsha, China
Jingni Xiao: Department of Nephrology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
Ya Zeng: Department of Gastroenterology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
Yueming Shen: Department of Gastroenterology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
Xueke Yu: Department of Gastroenterology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
Fei Zhu: Department of General Surgery, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
Jiao Qin: Department of Nephrology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China

DOI: https://doi.org/10.7717/peerj.16060
Journal volume & issue: Vol. 11
p. e16060

Abstract

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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.

Published in PeerJ

ISSN: 2167-8359 (Online)
Publisher: PeerJ Inc.
Country of publisher: United States
LCC subjects: Medicine; Science: Biology (General)
Website: https://peerj.com/

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