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Suppression of Hepatic Stellate Cell Activation by HJC0123, a Novel Small-Molecule Inhibitor of STAT3
Fredrick Bohanon^*, Xiaofu Wang, Omar Nunez Lopez, Sadhashiva Vasudevan, Haijun Chen, Jia Zhou, Ravi Radhakrishnan
University of Texas Medical Branch, Galveston, TX

Introduction: Signal transducer and activator of transcription 3 (STAT3) is involved in the regulation of angiogenesis, cell proliferation, differentiation, and apoptosis. Our previous work utilizing a fragment-based drug design approach has explored several novel scaffolds targeting STAT3 as potent anticancer agents, including HJC0123. In the present study, we tested HJC0123 compound in activated hepatic stellate cells (HSCs) for anti-fibrogenesis activity. HSC activation is characterized by accelerated proliferation and over-expression of α-smooth muscle actin (α-SMA), and is the major source for excessive extracellular matrix (ECM) production in hepatic fibrosis.
Methods: The cell viability of human and rat immortalized HSC cell lines LX-2 and HSC-T6 were measured by Alamar Blue assay. Cellular proteins were determined by immunoblotting and Immunofluorescence staining. Yo-pro-1 staining was used for apoptosis evaluation.
Results: HJC0123 treatment significantly inhibited LX-2 and HSC-T6 cells proliferation in a dose-dependent fashion, with attenuation of HSC activation marker α-SMA. HJC0123 induced S-phase cell cycle arrest and apoptosis. HJC0123 suppressed Tyr705-phosphorylated STAT3 (pStat3/T705), and impaired pStat3/T705 nuclear translocation and STAT3 transcriptional activity. STAT3 target genes cyclinD1 and c-myc were down-regulated by HJC0123.
In addition, the STAT3 inhibitor stattic suppressed LX-2 and HSC-T6 cells proliferation and α-SMA expression, confirming the role of STAT3 in the inhibition of HSC activation. Furthermore, HJC0123 suppressed endogenous and TGFβ-induced ECM protein fibronectin production in LX-2 cells.
Conclusion: HJC0123 inhibits HSC activation via a STAT3 pathway in vitro. HJC0123 represents a promising anti-hepatic fibrogenesis agent.

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