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

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.

The Role of TGF-β/SMAD Signaling in Hepatocellular Carcinoma: from Mechanism to Therapy and Prognosis

“…In the management of HCC, specific chemotherapeutic agents have demonstrated efficacy in halting tumor proliferation and metastasis by targeting the TGF-β/SMAD signaling cascade. Fluorofenidone (AKF-PD), an established drugs for idiopathic pulmonary fibrosis, also offers potential benefits for liver fibrosis by repressing HSC autophagy through the attenuation of the TGF-β1/SMAD pathway, potentially impeding the progression to HCC 128 . Sanguinarine (San), a natural benzo phenanthridine alkaloid, restrains tumor growth and HIF-1α signaling, and suppresses the expression changes of EMT markers as well as blocks p-SMAD2/3 translocation to the nucleus.…”

Hepatitis B virus X protein and TGF-β: partners in the carcinogenic journey of hepatocellular carcinoma

“…However, the clinical applicability and efficacy of these treatments require further validation through extensive clinical trials. Studies have shown that various chemotherapeutic agents, including Fluorofenidone (AKF-PD) ( 165 ), Sanguinarine (San) ( 166 ), Aspirin ( 167 ), Praziquantel (PZQ) ( 168 ), and Ursodeoxycholic acid (UDCA) ( 169 ), along with small molecule inhibitors such as Galunisertib (LY2157299) ( 170 – 172 ), LY2109761 ( 173 ), SKLB023 ( 174 ), and LY3200882 ( 175 ), are effective in treating HBV-HCC. The therapeutic vaccine Belagenpumatucel-L (Lucanix) ( 176 ) also exhibits efficacy in this setting.…”