期刊
RSC ADVANCES
卷 6, 期 102, 页码 100652-100663出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c6ra17459k
关键词
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资金
- National Institutes of Health, Cancer Prevention Research Institute of Texas award [P50 CA097007, P30 DA028821, R21 MH098344, T32-GM8256]
- R. A. Welch Foundation Chemistry and Biology Collaborative Grant from the Gulf Coast Consortia
- R. A. Welch Foundation Chemistry and Biology Collaborative Grant from the John Sealy Memorial Endowment Fund
- Center for Addiction Research from the University of Texas Medical Branch
- NATIONAL CANCER INSTITUTE [P50CA097007] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008256] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [P30DA028821] Funding Source: NIH RePORTER
Hepatic Stellate Cells (HSCs) are the major source of the excessive extracellular matrix (ECM) production that replaces liver parenchyma with fibrous tissue during liver fibrosis. The signal transducer and activator of transcription 3 (STAT3) promotes HCSs survival, proliferation, and activation contributing to fibrogenesis. We have previously used a fragment-based drug design approach and have discovered a novel STAT3 inhibitor, HJC0123. Here, we explored the biological effects of HJC0123 on the fibrogenic properties of HSCs. HJC0123 treatment resulted in the inhibition of HSCs proliferation at submicromolar concentrations. HJC0123 reduced the phosphorylation, nuclear translocation, and transcriptional activity of STAT3. It decreased the expression of STAT3-regulated proteins, induced cell cycle arrest, promoted apoptosis and downregulated SOCS3. HJC0123 treatment inhibited HSCs activation and downregulated ECM protein fibronectin and type I collagen expression. In addition, HJC0123 increased IL-6 production and decreased TGF-beta induced Smad2/3 phosphorylation. These results demonstrate that HJC0123 represents a novel STAT3 inhibitor that suppresses the fibrogenic properties of HSCs, suggesting its therapeutic potential in liver fibrosis.
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