Abstract
<title>Abstract</title> <p> <italic>Glycyrrhiza Uralensis Fisch. ex DC</italic> (GU) is a traditional medicinal plant widely used as a dietary supplement for the management of various diseases. Although previous studies have reported the pharmacological activities of GU and its bioactive constituents, its potential effects on chronic obstructive pulmonary disease (COPD) and the underlying mechanisms remain incompletely understood. This study investigated the therapeutic effects of wild GU root aqueous extract in a mouse model of COPD by integrating pharmacodynamic evaluation with gut microbiota analysis, metabolomics, network pharmacology, and molecular docking. Therapeutic efficacy was assessed through body weight, pulmonary function, lung histopathology, and serum inflammatory cytokine levels. Alterations in gut microbiota were analyzed using 16S rDNA sequencing, while metabolomics was performed to identify metabolites associated with GU treatment. Network pharmacology was used to predict potential therapeutic targets and signaling pathways, and molecular docking was conducted to evaluate the binding affinity between representative compounds and predicted target proteins. GU treatment significantly improved pulmonary function, attenuated lung inflammation, and restored the diversity and composition of the gut microbiota in COPD mice. Metabolomic analysis showed that GU treatment was associated with alterations in metabolic pathways, including phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, porphyrin metabolism, and fatty acid metabolism. Network pharmacology predicted that the PI3K-Akt signaling pathway and epidermal growth factor receptor (EGFR)-related pathways may be involved in the therapeutic effects of GU. Molecular docking suggested that several compounds, including liquiritin, mairin, sigmoidin-B, isoglycyrol, β-sitosterol, glabrene, glycyrin, isolicoflavonol, semilicoisoflavone B, quercetin, formononetin, kaempferol, and glyuranolide, exhibited favorable binding affinities toward the predicted hub targets AKT1, TNF, and EGFR. These findings demonstrate that GU alleviated COPD-related pathological changes in mice and suggest that modulation of gut microbiota, metabolic profiles, and multiple predicted molecular targets may contribute to its therapeutic effects. However, the proposed molecular mechanisms are based on computational predictions and association analyses and require further experimental validation. </p>