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Biochem Biophys Res Commun. 2019 May 21;513(1):49-55. doi: 10.1016/j.bbrc.2019.03.156. Epub 2019 Mar 29.

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

Author information

1
College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
2
Korea Mouse Phenotyping Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
3
College of Pharmacy, Gachon University, Incheon, Republic of Korea.
4
College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea. Electronic address: ysyoon@snu.ac.kr.
5
College of Pharmacy, Gachon University, Incheon, Republic of Korea. Electronic address: eyeball@gachon.co.kr.

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.

KEYWORDS:

Cirrhosis; Hepatic stellate cell; Liver fibrosis; STAT3; STX-0119

PMID:
30935693
DOI:
10.1016/j.bbrc.2019.03.156

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