Novel Axin Stabilizer YA6060 is a Promising Therapy for Liver Fibrosis

Abstract

<b>Abstract ID 17628</b> <b>Poster Board 115</b> Both Wnt/β-catenin and AMPK signaling pathways play an important role in liver fibrosis. We have previously synthesized a class of novel compounds that show dual activities of Wnt/β-catenin inhibition and AMPK activation <i>via</i> the mechanism of Axin stabilization. With our most recent lead compound YA6060, the aim of this study was to test the hypothesis that simultaneous Wnt/β-catenin inhibition and AMPK activation by a small molecule was a promising therapeutic strategy to treat liver fibrosis. The hepatic stellate cell line LX-2 was used to test the anti-fibrotic effects of YA6060 <i>in&nbsp;vitro</i>. The proliferation of LX-2 cells was determined by cell viability assay and wound healing assay. A mouse liver fibrosis model, established by intraperitoneal injection of dimethylnitrosamine (DMNA), was employed to validate the pharmacological effects of YA6060 <i>in&nbsp;vivo</i>. The expression of key proteins and genes were detected by Western blot and RT-PCR. Liver fibrosis was examined by Sirius Red staining. YA6060 treatment was found to suppress the proliferation of LX-2 cells and reduce the fibrotic and inflammatory gene expression. YA6060 treatment could also down-regulate the expression of β-catenin by stabilizing AXIN, leading to Wnt signaling inhibition, and simultaneously activate the AMPK pathway in LX-2 cells. Furthermore, YA6060 administration could significantly reduce the degree of liver fibrosis in mice, with the alteration in gene and protein expression that was consistent with the mechanism of Wnt inhibition and AMPK activation. In conclusion, our studies have showed that YA6060 can inhibit liver fibrosis by simultaneously inhibiting the Wnt/β-catenin signaling pathway and activating APMK signaling pathway. The findings have established that small molecule with dual activities of Wnt inhibition and AMPK activation <i>via</i> Axin stabilization is a valid strategy to the development of anti-fibrosis agents.