Uncovering the Pharmacological Mechanisms of Gexia-Zhuyu Formula (GXZY) in Treating Liver Cirrhosis by an Integrative Pharmacology Strategy

Abstract

Liver cirrhosis (LC) is a fibrotic lesion of liver tissue caused by the repeated progression of chronic hepatitis. The traditional Chinese medicine Gexia-Zhuyu formula (GXZY) has a therapeutic effect on LC. However, its pharmacological mechanisms on LC remain elucidated. Here, we used the network pharmacology approach to explore the action mechanisms of GXZY on LC. The compounds of GXZY were from the traditional Chinese medicine systems pharmacology (TCMSP) database, and their potential targets were from SwissTargetPrediction and STITCH databases. The disease targets of LC came from GeneCards, DisGeNET, NCBI gene, and OMIM databases. Then we constructed the protein-protein interaction (PPI) network to obtain the key target genes. And the gene ontology (GO), pathway enrichment, and expression analysis of the key genes were also performed. Subsequently, the potential action mechanisms of GXZY on LC predicted by the network pharmacology analyses were experimentally validated in LC rats and LX2 cells. A total of 150 components in GXZY were obtained, among which 111 were chosen as key compounds. The PPI network included 525 targets, and the key targets were obtained by network topological parameters analysis, whereas the predicted key genes of GXZY on LC were AR, JUN, MYC, CASP3, MMP9, GAPDH, and RELA. Furthermore, these key genes were related to pathways in cancer, hepatitis B, TNF signaling pathway, and MAPK signaling pathway. The in vitro and in vivo experiments validated that GXZY inhibited the process of LC mainly via the regulation of cells proliferation and migration through reducing the expression of MMP9. In conclusion, through the combination of network pharmacology and experimental verification, this study offered more insight molecular mechanisms of GXZY on LC.