A novel STAT3 inhibitor, STX-0119, attenuates liver fibrosis by inactivating hepatic stellate cells in mice.

Abstract

Liver fibrosis is characterized by formation of scar tissue in the liver. The role of STAT3 signaling has been implicated on activating hepatic stellate cells (HSC) to myofibroblast-like cells in liver fibrosis. Major factors that activate STAT3 signaling are TGF-β1 and IL-6, which are upregulated in the liver in patients afflicted with liver fibrosis. Recent reports indicate that not only IL-6, but also the non-canonical signaling pathway of TGF-β1 is associated with STAT3 signaling. In this study, we demonstrate a new function of the STAT3 inhibitor, STX-0119, in liver fibrosis. STX-0119 is an inhibitor of STAT3 dimerization, which is required for nuclear localization of STAT3. We first investigated the anti-fibrotic effect of STX-0119 in in vitro experiments. Exposure to STX-0119 inhibited the nuclear localization of STAT3 in HSCs, resulting in decreased expression of its target genes, such as col1a1 and αSMA. In addition, STX-0119 also inhibited the TGF-β1/IL-6-induced activation of HSCs. Next, we examined the in vivo effect of STX-0119 in the liver fibrosis mouse model using thioacetamide (TAA) and carbon tetrachloride (CCl4). STX-0119 attenuated the TAA-induced liver fibrosis by inhibiting activation of HSCs to myofibroblast-like cells. Consistent with the in vivo results using TAA-induced liver fibrosis model, treatment of STX-0119 similarly attenuated CCl4-induced liver fibrosis. In conclusion, we believe that STX-0119 inhibits the development of liver fibrosis by blocking the activation of hepatic stellate cells. These results indicate that STX-0119 is a potential new therapeutic strategy to prevent disease progression to cirrhosis.

• Authors: Seungho Choi, Hyun Jin Jung, Min Woo Kim, Ju-Hee Kang, Dongyun Shin, Yeong-Su Jang, Yeo Sung Yoon, Seung Hyun Oh
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 513 Issue 1 Pg. 49-55 (05 21 2019) ISSN: 1090-2104 [Electronic] United States
• PMID: 30935693 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Oxadiazoles
• Quinolines
• STAT3 Transcription Factor
• STX-0119
• Collagen

Topics

• Animals
• Cell Proliferation (drug effects)
• Collagen (analysis)
• Hepatic Stellate Cells (drug effects, pathology)
• Liver Cirrhosis (drug therapy, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Oxadiazoles (therapeutic use)
• Quinolines (therapeutic use)
• STAT3 Transcription Factor (antagonists & inhibitors)