Aug 2026· Current Computer - Aided Drug Design· Vol 22· 0 citations
Medicine
TL;DR
The findings suggest that YFC may exert therapeutic effects in stable COPD through multi-component, multi-target regulation of the PI3K-Akt pathway and related inflammatory signaling networks.
Abstract
INTRODUCTION
Yifei Capsule (YFC), a Traditional Chinese Medicine (TCM) formulation, has shown clinical benefit in patients with stable Chronic Obstructive Pulmonary Disease (COPD). However, its molecular mechanisms remain insufficiently understood. This study aimed to systematically investigate the active compounds, key targets, and signaling pathways underlying the therapeutic effects of YFC in stable COPD by integrating computational pharmacology with single-cell transcriptomic validation.
Methods
An integrated workflow combining network pharmacology, molecular docking, and 100 ns Molecular Dynamics (MD) simulations was used to identify bioactive compounds, candidate therapeutic targets, and major signaling pathways of YFC. To externally validate the in silico findings, an independent public single-cell RNA sequencing (scRNA-seq) dataset (GSE249584) containing 54,821 cells from 15 human samples (7 controls and 8 COPD patients) was analyzed to characterize the cell-type-specific expression patterns of hub genes in COPD.
Results
A total of 167 bioactive compounds in YFC and 977 putative targets were identified, of which 222 overlapped with COPD-related targets. Network topology analysis identified SRC, PIK3R1, and STAT3 as major hub genes, and KEGG enrichment analysis indicated that these targets were primarily enriched in the PI3K-Akt signaling pathway (hsa04151, p = 1.23E-15). Molecular docking revealed strong binding affinities between representative compounds and core targets, while MD simulations confirmed the dynamic stability of key complexes, particularly SRC-Korseveriline. scRNA-seq analysis further demonstrated cell-type-specific dysregulation of hub genes in COPD: STAT3 was significantly upregulated in monocyte/macrophage populations (adjusted p = 6.59E-08, log2FC = 0.32), PIK3R1 was downregulated in T cells (adjusted p = 2.05E-20, log2FC = -0.41), and SRC showed bimodal expression, with upregulation in endothelial cells (adjusted p = 0.002, log2FC = 0.38) but downregulation in T cells (adjusted p = 0.03, log2FC = -0.27).
Discussion
These findings suggest that YFC may exert therapeutic effects in stable COPD through multi-component, multi-target regulation of the PI3K-Akt pathway and related inflammatory signaling networks. The cell-type-specific dysregulation of SRC, PIK3R1, and STAT3 supports a nuanced immunomodulatory and vascular-regulatory mechanism, highlighting the value of integrating computational prediction with single-cell transcriptomic evidence.
Conclusion
This multi-scale study provides a mechanistic framework for understanding the action of YFC in stable COPD and identifies SRC, PIK3R1, and STAT3 as plausible core targets. The results support the utility of combining network pharmacology, molecular simulation, and single-cell transcriptomics to dissect the mechanisms of complex herbal medicines. Nevertheless, the present findings remain correlative and require further experimental validation to establish causality.
Chronic obstructive pulmonary disease (COPD) remains a major global health challenge. This study explored the therapeutic mechanisms of Huangjing (Polygonati Rhizoma) and Gegen (Puerariae Lobatae Radix), two food-medicine homologous herbs with potential in COPD management. Integrating network pharmacology, serum pharmacochemistry, molecular docking, and experimental validation, we identified 239 shared targets and the PI3K/AKT pathway as a potential key mechanism. UHPLC Q-Exactive Orbitrap MS revealed 66 compounds, 14 of which were absorbed into circulation. In vivo, Huangjing-Gegen appeared to improve lung function (PaO2 increased by 28.3%, PaCO2 decreased by 22.7%), alleviate pathology, and reduce inflammation through downregulating TNF-α (by 21.4%), IL-6 (by 30.7%), and IL-1β (by 29.3%) and suppressing the EGFR-PI3K/AKT pathway. Molecular docking provided supportive evidence for strong binding between absorbed puerarin derivatives and core targets. These findings suggest that the PI3K/AKT pathway may play a central role in the therapeutic effects of Huangjing-Gegen against COPD.
Shaoqing Zhu, Jiaruo Li, Lin Chu et al.· Natural Product Research· 0 citations
Background Chronic obstructive pulmonary disease (COPD)-associated sarcopenia is a critical comorbidity associated with high morbidity and mortality, driven by chronic systemic inflammation, oxidative stress, and proteometabolic dysregulation. The Astragalus membranaceus-Ginseng (HQ-RS) herbal pair is a traditional remedy for consumptive diseases; however, its molecular mechanisms against this comorbidity remain undefined. Methods We integrated transcriptomic data from four Gene Expression Omnibus (GEO) datasets (two discovery cohorts and two validation cohorts) for COPD and sarcopenia. Differentially expressed genes (DEGs) were identified using the thresholds of P < 0.05 and —log2FC— ≥ 1. Active compounds of HQ-RS were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database (oral bioavailability (OB) ≥ 30%, drug-likeness (DL) ≥ 0.18). Candidate targets were identified by intersecting drug targets with shared disease targets (GeneCards relevance score > 20). A protein-protein interaction (PPI) network was constructed to identify hub genes using multi-centrality metrics. Molecular docking was performed with celecoxib as a positive control. Three independent 100 ns molecular dynamics (MD) simulations of the FMNT-PTGS2 complex were then performed, and the trajectories were analyzed using the Simulation Interaction Diagram (SID) tool. Results We identified 1,267 COPD-specific and 115 sarcopenia-specific DEGs, yielding nine shared DEGs. Intersection of drug targets with 279 shared disease targets identified 36 candidate targets. PPI network analysis highlighted PTGS2, CDKN1A, NFE2L2, NOS3, and MMP2 as key hub genes. Molecular docking revealed that formononetin (FMNT) exhibited the most favorable binding affinity to PTGS2 (−8.94 kcal/mol), comparable to the positive control celecoxib (−7.97 kcal/mol). Three independent 100 ns MD simulations of the FMNT-PTGS2 complex demonstrated that the system reached dynamic equilibrium after approximately 20 ns in all replicates, with the ligand maintaining a stable binding pose throughout the simulations. Molecular Mechanics Generalized Born Surface Area (MM-GBSA) calculations across three replicate simulations yielded a mean binding free energy of −47.82 ± 1.13 kcal/mol, supporting the thermodynamic favorability of the interaction. Protein-ligand interaction analysis identified sustained hydrogen bonds and hydrophobic contacts with key active-site residues. Conclusion This study computationally predicts that the FMNT-PTGS2 interaction may represent a potential mechanism underlying the efficacy of the HQ-RS herbal pair in treating COPD-associated sarcopenia. This study is entirely computational and limited by small discovery cohort sample sizes (COPD n = 6, sarcopenia n = 51). These findings provide a multi-component, multi-target mechanistic hypothesis that requires experimental validation.
Xiao-Weng Wu, Jiaxian Li, Jianan He et al.· PeerJ· 0 citations
ETHNOPHARMACOLOGICAL RELEVANCE
Bupi Yichang Pill (BYP) is a traditional Chinese medicine (TCM) formula with an established clinical history in managing chronic intestinal disorders and has shown promising protective effects against ulcerative colitis (UC). However, its pharmacodynamic basis and underlying molecular mechanisms remain poorly characterized.
AIM OF THE STUDY
This study systematically investigated the pharmacological basis and mechanistic underpinnings of BYP in UC through an integrated strategy combining network pharmacology, multi-omics profiling, and experimental validation.
MATERIALS AND METHODS
A dextran sulfate sodium (DSS)-induced murine UC model was used to evaluate BYP's protective effects, with disease severity assessed by body weight, disease activity index (DAI), colon length, and histopathology, and inflammatory responses quantified by ELISA and RT-qPCR. Chemical constituents were characterized by UPLC-HRMS, and bioactive compounds, targets, and pathways were identified through network pharmacology and molecular docking. Gut microbiota composition, metabolic profiles, and transcriptomic changes were interrogated by 16S rRNA sequencing, untargeted metabolomics, and RNA-seq, respectively. The PI3K/Akt/IKK/NF-κB axis was validated by Western blotting and immunofluorescence in colonic tissues and LPS-stimulated RAW264.7 macrophages.
RESULTS
BYP significantly attenuated DSS-induced colitis, as evidenced by reduced body weight loss, lower DAI scores, preserved colon length, and alleviated mucosal injury. BYP markedly decreased TNF-α, IL-1β, and IL-6 levels while upregulating IL-10. UHPLC-HRMS identified 115 constituents, of which eight-including kaempferol, liquiritin, quercetin, berberine, paeoniflorin, cryptopine, perlolyrine, and glabrone-were prioritized as overlapping bioactive compounds. Network pharmacology implicated key targets including IL6, TNF, AKT1, and PTGS2, and molecular docking confirmed favorable binding affinities. KEGG enrichment highlighted the PI3K/Akt and NF-κB pathways as principal regulatory axes. Multi-omics analysis revealed that BYP restored gut microbiota dysbiosis, ameliorated bile acid and amino acid metabolism, and modulated the expression of inflammation- and barrier-related genes. Western blotting confirmed suppression of PI3K, Akt, IKK, and NF-κB p65 phosphorylation, corroborated by immunofluorescence in both colonic tissue and macrophages.
CONCLUSION
BYP confers protection against DSS-induced ulcerative colitis through a multi-component, multi-target, and multi-level regulatory mechanism. Kaempferol and liquiritin emerge as principal bioactive contributors, acting through UC-associated molecular targets and inflammatory signaling cascades. Integrated multi-omics analyses and experimental validation collectively demonstrate that BYP ameliorates gut microbial and metabolic dysregulation while suppressing PI3K/Akt/IKK/NF-κB pathway activation, providing both a mechanistic basis and pharmacological rationale for its traditional clinical use in UC management.
Yunlu Zou, Zi-Zhao Yang, Jiatong Liu et al.· Journal of Ethnopharmacology· 0 citations
This study aimed to elucidate the therapeutic mechanisms of Chai Gui Zexie Decoction against non-small cell lung cancer (NSCLC) through an integrated approach combining metabolomics, network pharmacology, and experimental validation. A subcutaneous NSCLC metastasis model was established in C57BL/6 mice using Lewis lung cancer cells. Mice were randomly assigned to model, low-dose, and high-dose Chai Gui Zexie Decoction groups (n = 6 per group). Tumor growth was monitored over 18 days. Serum metabolomics analysis using liquid chromatography-tandem mass spectrometry was performed to identify differential metabolites and blood-absorbed components. Network pharmacology was employed to predict therapeutic targets, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Western blotting was conducted to validate the expression of core targets (IGF1R, PTK2, SRC) in tumor tissues. High-dose Chai Gui Zexie Decoction significantly inhibited tumor growth compared to the model group (P < 0.05). Metabolomics identified 13 blood-absorbed components, primarily enriched in phenylalanine metabolism. Network pharmacology revealed 195 overlapping targets between the decoction and NSCLC, with 10 core targets identified, including SRC, PTK2, and IGF1R. KEGG analysis implicated key pathways such as PI3K-Akt signaling, EGFR TKI resistance, and Ras/MAPK signaling. Western blot validation confirmed that high-dose treatment significantly downregulated IGF1R, PTK2, and SRC protein expression in tumor tissues (P < 0.05). Chai Gui Zexie Decoction exerts therapeutic effects against NSCLC through a multi-component, multi-target mechanism involving the regulation of RTK signaling pathways and phenylalanine metabolism. These findings provide a scientific basis for its clinical application and highlight potential therapeutic targets for NSCLC treatment.
INTRODUCTION
Antipsychotic-induced hyperprolactinemia (HPRL) is a prevalent and troubling side effect that impairs treatment adherence. Xuefu Zhuyu Pills (XFZY), a traditional Chinese medicine formula, have shown efficacy in clinical practice; however, their active components and mechanisms of action remain unknown.
METHODS
We identified the components of XFZY in human plasma by UPLC-Q-TOF-MS/MS and performed network pharmacology analysis to screen key targets and core active components through topological analysis. Intersecting targets were subjected to GO and KEGG enrichment analyses on Metascape, followed by molecular docking and molecular dynamics simulations to assess binding stability between core active components and key targets.
RESULTS
A total of 67 absorbed components were found in human plasma. Based on the network pharmacology results, we identified seven core targets (AKT1, ESR1, IL6, TNF, ERBB2, CTNNB1, and MAOA) and three potential active ingredients (Makisterone B, 3-O-beta-Dglucopyranosylplatycodigenin, and 4',5,6,7-Tetramethoxyflavone). GO and KEGG suggested that hormone level regulation, the neuroactive ligand-receptor interaction, the apelin signaling pathway, and the cGMP-PKG signaling pathway may play key roles in treating HPRL caused by antipsychotic drugs.
DISCUSSION
Molecular docking results showed that the core active ingredient binds well with the key targets, and molecular dynamics simulations further verified their stability.
CONCLUSION
This study preliminarily revealed the components in human plasma of XFZY in HPRL treatment and their potential pharmacological mechanism. These findings provide a scientific basis for clinical studies.
Mingyue Liu, Zihuan Zhang, Guanli Su et al.· Combinatorial chemistry & hi...· 0 citations
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, with limited therapeutic efficacy due to tumor heterogeneity in conventional treatments. In the present study, an integrative, network pharmacology approach was employed to elucidate the multi-target mechanism of action of phytochemicals derived from Glossocardia bosvallia against NSCLC. Among 38 phytocompounds identified, 31 compounds that satisfied pharmacokinetic properties were selected for subsequent analysis. Ligand-based target prediction identified 429 potential protein targets, which are integrated with the top 250 differentially expressed genes obtained from the GSE33532 dataset. Intersection analysis identified eight therapeutic targets: PTGES, SRD5A1, CDK1, KIF11, TOP2A, CDC45, MB, and CHEK1. Protein-protein interaction and enrichment analyses demonstrated that these targets are predominantly involved in cell cycle regulation, mitotic cell cycle, and DNA replication pathways. Gene expression analysis demonstrated significant overexpression of the prioritized targets in NSCLC tissues, while survival analysis identified CHEK1 as the gene significantly associated with survival (p < 0.05). Molecular docking identified TOP2A_quinic acid as the most favorable complex, exhibiting a binding affinity of -12.27 kcal/mol, KIF11_linoleic acid as -12.10 kcal/mol and CHEK1_2,3-dihydro-3,5-dihydroxy-6-methyl-4h-pyran-4-one as -6.75 kcal/mol, which was further validated by dynamic simulations, principal component analysis based free energy landscape, and DSSP analysis, confirming the stability of the protein. This integrative framework provides a robust strategy for identifying biologically relevant and therapeutically actionable targets supporting the potential of G. bosvallia-derived phytochemicals as promising candidates for NSCLC.
S. Kulandhaivel, A. Stalin, Pandiyan Muthuramalingam et al.· Computational biology and ch...· 0 citations