Exploring the Mechanism of Gancao (Glycyrrhizae Radix et Rhizoma) Nourishing-Yin Decoction in Intervening Elderly Primary Sjögren's Syndrome Based on Network Pharmacology and Molecular Docking

Abstract

Based on network pharmacology and molecular docking, this study aimed to predict the potential active ingredients, core targets, and signaling pathways of Gancao (Glycyrrhizae Radix et Rhizoma) Nourishing-Yin Decoction (GCNY) against elderly primary Sjögren's syndrome (EpSS) and to explore its underlying molecular mechanisms.

Active ingredients of GCNY were identified by mass spectrometry in our previous work, and corresponding ingredient targets were predicted via the TCMSP platform. Disease targets related to aging and primary Sjögren's syndrome were retrieved from the GeneCards database. Intersection analysis was performed to obtain common drug-disease targets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed using Metascape. A protein–protein interaction (PPI) network was constructed through the STRING database, and core targets were screened by Cytoscape software. Finally, molecular docking was performed to validate the top-five core targets ranked by degree value and representative active ingredients.

A total of 79 unique active ingredients were identified from GCNY, corresponding to 994 potential therapeutic targets. Seventy-one common drug-disease targets were obtained. Twenty-six core targets were identified by PPI network analysis, among which signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor (TNF), AKT serine/threonine kinase 1 (AKT1), tumor protein p53 (TP53), and interleukin-6 (IL-6) exhibited the highest degree values. GO enrichment terms included response to lipopolysaccharide, positive regulation of protein phosphorylation, membrane raft, and endopeptidase activity. Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed significant enrichment in lipid and atherosclerosis pathway, AGE-RAGE signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, and apoptosis pathway. Molecular docking results demonstrated favorable binding affinities between active ingredients and core targets. The binding energies of ginsenoside Rg1 against AKT1 and STAT3 were −6.9 and −7.3 kcal/mol, respectively. Isoliquiritin yielded binding energies of −8.0 kcal/mol for TNF and −6.3 kcal/mol for TP53, whereas oleanolic acid bound to IL-6 with a binding energy of −8.1 kcal/mol, suggesting that the active ingredients exhibit favorable binding affinity for the core targets.

GCNY may exert adjuvant therapeutic effects on EpSS via multiple active constituents including ginsenoside Rg1, isoliquiritin, and oleanolic acid. These ingredients act on core targets such as STAT3, TNF, AKT1, TP53, and IL-6 and modulate multiple signaling pathways including lipid-atherosclerosis and AGE-RAGE pathways to produce anti-inflammatory, immunoregulatory, and apoptosis-modulating activities.