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CN 22-1108/R
Volume 42 Issue 6
Jun.  2026
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Article Navigation >  Journal of Clinical Hepatology  > 2026  >  42(6): 1310-1320

Effect and mechanism of the azo-podophyllotoxin derivative SU056 in a mouse model of carbon tetrachloride-induced liver fibrosis

DOI: 10.12449/JCH260612

  • Department of Gastroenterology，Shanghai General Hospital，Shanghai Jiao Tong University School of Medicine，Shanghai 200080，China

Research funding:

General Project of National Natural Science Foundation of China (82170620);

Wang Bao-en Liver Fibrosis Foundation (CFHPC2024026)

More Information
  • Corresponding author: LU Lungen， lungenlu1965@163.com （ORCID： 0000-0002-1533-4068）
  • Received Date: 2026-01-04
  • Accepted Date: 2026-02-06
  • Published Date: 2026-06-25
    Abstract
  •   Objective  To investigate the effect of SU056， an azo-podophyllotoxin derivative， on carbon tetrachloride （CCl4）-induced liver fibrosis in mice and related mechanisms of action.  Methods  A total of 12 mice were randomly divided into control group， model group （CCl4+normal saline）， and treatment group （CCl4+SU056）， with 4 mice in each group. Mice were given intraperitoneal injection of CCl4 to establish a model of liver fibrosis， and during the middle stage of modeling， the mice in the treatment group were given daily intraperitoneal injection of SU056. Liver histopathological injury， collagen deposition， and liver function were assessed based on HE staining， Masson staining， Sirius Red staining， the content of hydroxyproline in liver tissue， and the serum levels of alanine aminotransferase and aspartate aminotransferase， and immunofluorescence assay was used to measure the expression levels of smooth muscle actin α （α-SMA）， collagen type Ⅰ， and Y-box binding protein 1 （YB1）. The human hepatic stellate cell （HSC） line LX-2 and primary mouse HSC were used， and CCK-8 assay was used to measure cell proliferation； Transwell assay was used to observe cell migration； quantitative reverse transcription-polymerase chain reaction and Western Blot were used to measure the expression levels of collagen type Ⅰ， collagen type Ⅲ， YB1， phosphorylated mammalian target of rapamycin （mTOR）， and phosphorylated S6K， so as to validate the function of the YB1/mTOR signaling axis. The one-way or two-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups.  Results  In the mouse model of liver fibrosis induced by CCl4， compared with the model group， the treatment group had significant alleviation of inflammatory cell infiltration， collagen deposition， and pseudolobule formation in liver tissue and significant reductions in the serum levels of alanine aminotransferase and aspartate aminotransferase and the content of hydroxyproline in liver tissue （all P<0.01）. Immunofluorescence assay showed that SU056 significantly inhibited the abnormal high expression of α-SMA， collagen type I， and YB1 in liver tissue （all P<0.01）. In vitro experiments showed that SU056 inhibited the transforming growth factor-β1-induced proliferation of LX-2 cells （P<0.01）， the migration of LX-2 cells （P<0.05）， and the transcriptional up-regulation of collagen type Ⅰ and collagen type Ⅲ （all P<0.05） in a dose-dependent manner， and SU056 could inhibit the spontaneous activation of primary HSC in vitro. Mechanistic studies revealed that transforming growth factor-β1 simultaneously upregulated the expression levels of YB1， phosphorylated mTOR， and phosphorylated S6K in LX-2 cells， and treatment with SU056 （10 and 20 µmol/L） could downregulate the protein expression levels of collagen type I， YB1， phosphorylated mTOR， and phosphorylated S6K. Specific knockdown of YB1 or administration of the mTOR inhibitor rapamycin exerted a similar effect as SU056. SU056 also inhibited the co-upregulation of α-SMA and phosphorylated mTOR in liver tissue of model mice （P<0.01）.  Conclusion  SU056 can effectively inhibit HSC activation， proliferation， migration， and extracellular matrix production both in vivo and in vitro and thus delay the progression of liver fibrosis， by disrupting the YB1/mTOR positive feedback signaling axis.

     

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