Network Pharmacology-Based Analysis on the Potential Biological Mechanisms of Sinisan Against Non-Alcoholic Fatty Liver Disease.

Xiaoyi Wei,Xueqian Wang,Peng Fang,Qiuyun Zhang,Fafeng Cheng,Jiayang Sai,Jiajun Liang,Zisong Wang,Qingguo Wang,Chongyang Ma,Weixin Hou,Bo Dou,Tian Xu

doi:10.3389/fphar.2021.693701

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in China. Sinisan (SNS) is a traditional Chinese medicine formula that has been widely used in treating chronic liver diseases, including NAFLD. However, its underlying biological mechanisms are still unclear. In this study, we employed a network pharmacology approach consisting of overlapped terms- (genes or pathway terms-) based analysis, protein-protein interaction (PPI) network-based analysis, and PPI clusters identification. Unlike the previous network pharmacology study, we used the shortest path length-based network proximity algorithm to evaluate the efficacy of SNS against NAFLD. And we also used random walk with restart (RWR) algorithm and Community Cluster (Glay) algorithm to identify important targets and clusters. The screening results showed that the mean shortest path length between genes of SNS and NAFLD was significantly smaller than degree-matched random ones. Six PPI clusters were identified and ten hub targets were obtained, including STAT3, CTNNB1, MAPK1, MAPK3, AGT, NQO1, TOP2A, FDFT1, ALDH4A1, and KCNH2. The experimental study indicated that SNS reduced hyperlipidemia, liver steatosis, and inflammation. Most importantly, JAK2/STAT3 signal was inhibited by SNS treatment and was recognized as the most important signal considering the network pharmacology part. This study provides a systems perspective to study the relationship between Chinese medicines and diseases and helps to discover potential mechanisms by which SNS ameliorates NAFLD.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease with a global prevalence of 25% (Cotter and Rinella, 2020)
gene ontology (GO) enrichment indicated that SNS targets and NAFLD genes could be enriched in the same GO terms with statistically significant difference (Figures 3B–D)
These results showed similar terms enriched with SNS targets and NAFLD genes, indicating potential therapeutic effects of SNS against NAFLD

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease with a global prevalence of 25% (Cotter and Rinella, 2020). Increased NAFLD-related mortality has been observed in several studies from the past years (Allen et al, 2019; Targher et al, 2020). Even simple steatosis might result in increased all-cause mortality because of the progression of this disease after a follow-up observation over decades (Tilg and Targher, 2020). NAFLD includes various clinical phenotypes ranging from simple steatosis (a benign condition called fatty liver) to non-alcoholic steatohepatitis (NASH) and hepatic fibrosis. These conditions increase the risks of liver-related complications, such as cirrhosis, liver failure, and hepatocellular carcinoma. It has to be acknowledged that control of this disease would have a major impact on the benefits of health care

Methods

Results

Conclusion