Action Mechanism Underlying Improvement Effect of Fuzi Lizhong Decoction on Nonalcoholic Fatty Liver Disease: A Study Based on Network Pharmacology and Molecular Docking

Abstract

Objective: This study aimed to decipher the bioactive compounds and potential mechanism of traditional Chinese medicine (TCM) formula Fuzi Lizhong Decoction (FLD) for nonalcoholic fatty liver disease (NAFLD) treatment via an integrative network pharmacology approach.

Methods: The candidate compounds of FLD and its relative targets were obtained from the TCMSP and PharmMapper web server, and the intersection genes for NAFLD were discerned using OMIM, GeneCards, and DisGeNET. Then, the PPI and component-target-pathway networks were constructed. Moreover, GO enrichment and KEGG pathway analysis were performed to investigate the potential signaling pathways associated with FLD's effect on NAFLD. Eventually, molecular docking simulation was carried out to validate the binding affinity between potential core components and key targets.

Results: A total of 143 candidate active compounds and 129 relative drug targets were obtained, in which 61 targets were overlapped with NAFLD. The PPI network analysis identified ALB, MAPK1, CASP3, MARK8, and AR as key targets, mainly focusing on cellular response to organic cyclic compound, steroid metabolic process, and response to steroid hormone in the biological processes. The KEGG pathway analysis demonstrated that 16 signaling pathways were closely correlated with FLD's effect on NALFD with cancer pathways, Th17 cell differentiation, and IL-17 signaling pathways as the most significant ones. In addition, the molecular docking analysis revealed that the core active compounds of FLD, such as 3'-methoxyglabridin, chrysanthemaxanthin, and Gancaonin H, had a high binding activity with such key targets as ALB, MAPK1, and CASP3.

Conclusions: This study suggested that FLD exerted its effect on NAFLD via modulating multitargets with multicompounds through multipathways. It also demonstrated that the network pharmacology-based approach might provide insights for understanding the interrelationship between complex diseases and interventions of the TCM formula.

Figure 1

Detailed flowchart of the study design.

Figure 2

Compound-target network: pink circles represent the herbs in FLD; hexagons represent active compounds of each herb, and A1, B1, and C1 hexagons correspond to active compounds shared by different herbs; blue diamonds represent related targets (the IDs of the components are presented in Table 1).

Figure 3

Venn's diagram of intersection targets of FLD and NAFLD.

Figure 4

PPI network of FLD for NAFLD treatment. Each node represents a protein target, and each edge symbolizes the interaction between two nodes. The PPI network diagram is arranged according to the df. The greater the significance, the more central the node is.

Figure 5

The 20 most significant of GO analysis (a) for BP, (b) for CC and (c) for MF and pathway enrichment (d) KEGG analysis of therapeutic target genes of FLD on NFALD.

Figure 6

Component-target-pathway network. Green represents active ingredients of FLD; blue represents targets; dark blue represents signaling pathways of NAFLD.

Figure 7

3D structure diagram of the top three target proteins.

Figure 8

Molecular docking of 3′-methoxyglabridin and ALB. The dashed blue lines represent hydrogen bonds.

Figure 9

Potential target proteins of FLD regulating NAFLD on the predicted pathways (the pink nodes are potential target proteins of FLD, and the green nodes are relevant targets in the pathway).