Elucidating the molecular mechanisms of paeoniflorin intervention in oral lichen planus: a computational biology and bioinformatics–based research strategy
This study provides a systems-level map of PF’s multi-target intervention in OLP, highlighting a composite anti-inflammatory–immune reprogramming–pro-repair axis centered on core inflammatory kinases and proteases.
Abstract
Background Oral lichen planus (OLP) is a chronic inflammatory mucosal disease with a risk of malignant transformation and limited long-term therapeutic options. Paeoniflorin (PF), a natural monoterpene glycoside, exhibits multi-target anti-inflammatory and immunomodulatory properties, but its systematic mechanisms against OLP remain elusive. Methods We employed an integrative framework combining network pharmacology, transcriptomic cross-validation, molecular docking, and molecular dynamics (MD) simulations. Public databases were mined to identify PF targets and OLP-related genes. Core targets were prioritized via protein-protein interaction (PPI) network topology and further validated using OLP tissue transcriptomic datasets (GSE52130 and GSE213349). Functional enrichment analyses were performed, followed by structural validation of PF–target binding via molecular docking and 100-ns MD simulations. Results Sixty-eight overlapping targets between PF and OLP were identified. PPI network analysis and transcriptomic cross-validation pinpointed eight core targets: AKT1, IL6, MMP9, STAT3, TNF, IL1B, PTGS2, and PDE4B. Mechanistically, these targets converged on the TNF, PI3K–Akt, and MAPK signaling pathways, regulating inflammatory response, cell migration, apoptosis, and protease activity at membrane microdomain and extracellular matrix interfaces. Molecular docking showed PF binding affinities comparable to or exceeding reference inhibitors (e.g., STAT3: −9.27 vs. Stattic −9.16 kcal/mol). MD simulations confirmed stable conformational binding, with the STAT3 and PDE4B complexes exhibiting the most balanced rigidity and lowest ligand RMSD (0.09–0.10 nm). Conclusion This study provides a systems-level map of PF’s multi-target intervention in OLP, highlighting a composite anti-inflammatory–immune reprogramming–pro-repair axis centered on core inflammatory kinases and proteases. The structural validation of key targets establishes a mechanistic rationale for PF as a promising therapeutic candidate, warranting further preclinical and clinical development for OLP management.
Hepatocellular carcinoma (HCC) is an aggressive malignancy with limited therapies. We explored the anti-HCC mechanisms of Zanthoxylum nitidum (Roxb.) DC. via network pharmacology, bioinformatics and molecular docking. We identified its active components, targets and HCC-related key genes by differential expression analysis. Enrichment analysis showed these targets act in HCC-related pathways like alcoholic liver disease and the PPAR signalling pathway. Machine learning screened 5 characteristic genes (ESR1, CCNA2, CYP2B6, CHRM2, IL10), among which ESR1 and CCNA2 correlate with patient prognosis. These genes regulate tumour microenvironment and show epigenetic variations in methylation and copy number. Molecular docking confirmed stable binding between plant components and core targets. This study first reveals the multi-target anti-HCC mechanisms of Z. nitidum, offering evidence for its clinical use. Follow-up experiments are needed to validate our findings.
Rongjie Zhang, Ge Zhou, Jinhai Luo et al.· Artificial Cells Nanomedicin...· 0 citations
Aim Given the limited availability of safe and effective treatments for inflammatory bowel disease (IBD), we applied an integrated network pharmacology approach to systematically map the targets and pathways of cordycepin, a bioactive compound from Cordyceps militaris, in experimental colitis. Methods Cordycepin was administered intraperitoneally during dextran sulfate sodium (DSS) exposure in mice, with efficacy evaluated by the disease activity index (DAI) and histopathological analysis. Network pharmacology analysis (TCMSP, CTD, SEA, BATMAN-TCM, GeneCards, and PharmMapper), molecular docking, and molecular dynamics (MD) simulations were performed to identify and validate potential core targets. AKT1 and tight junction protein ZO-1 expression in colonic tissues was assessed by immunohistochemistry (IHC). The involvement of AKT signaling in cordycepin’s effects on tight junction integrity and mitochondrial function was further investigated in lipopolysaccharide (LPS)-treated Caco-2 cells using the AKT inhibitor MK2206. Results Cordycepin (50 mg/kg) significantly attenuated body weight loss and DAI elevation in DSS-treated mice. A total of 361 putative cordycepin-related targets were identified from six public databases, while 2, 072 UC-related targets were obtained from GeneCards, OMIM, and DisGeNET. A total of 199 overlapping targets were functionally enriched in processes including “TNF signaling pathway”, “PI3K-AKT signaling pathway” and “cellular response to lipopolysaccharide”. The PPI network identified 8 core targets, among which AKT1, NFKB1, RELA and TP53 demonstrated strong binding affinity (binding free energy<-6.0 kcal/mol) with cordycepin in molecular docking and were enriched within the PI3K/AKT pathway. IHC analysis showed that cordycepin reversed alterations of colonic AKT1 and ZO-1 levels in DSS mice. In Caco-2 cells, AKT inhibition with MK2206 attenuated the protective effects on tight junction integrity and mitochondrial function against LPS-induced injury. Conclusion These findings suggest that prophylactic administration of cordycepin, a promising natural compound, alleviates experimental colitis, potentially through modulation of the PI3K/AKT1 signaling pathway and restoration of epithelial barrier integrity.
Wenting Zhang, Minyan Qian, Wenwei Jiang et al.· Journal of Inflammation Rese...· 0 citations
Gout is a disease characterized by hyperuricemia and the deposition of urate crystals in joints and soft tissues, leading to recurrent acute arthritis. Its increasing prevalence imposes substantial clinical and socioeconomic burdens. Sishen Decoction (SSD) has been used in the treatment of gout, but its potential molecular mechanisms remain unclear. This study applied an integrated network pharmacology and molecular docking approach to identify potential targets and signaling pathways associated with SSD in gout. Active compounds and corresponding targets of SSD were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), while gout-related targets were collected from the GeneCards and Online Mendelian Inheritance in Man (OMIM) databases. Overlapping targets were identified and used to construct a drug-component-target-disease network. A protein-protein interaction (PPI) network was established using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed, followed by molecular docking using the docking server analysis module. A total of 37 bioactive compounds were associated with 116 overlapping gout-related targets. The top hub targets included TP53, IL6, IL1B, TNF, AKT1, EGFR, CASP3, JUN, BCL2, and MMP9. GO analysis suggested that these targets are involved in gene expression regulation and signal transduction. KEGG enrichment analysis indicated significant associations with the mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase/protein kinase B (PI3K-Akt), interleukin-17 (IL-17), and tumor necrosis factor (TNF) signaling pathways. Molecular docking predicted favorable interactions between key compounds and hub targets, with all binding energies of ≤-5 kcal/mol. These computational findings provide potential mechanistic hypotheses for the action of SSD in gout and may support future experimental validation.
Tingting Zhou, Xiandong Liang· Journal of Visualized Experi...· 0 citations
Chronic glomerulonephritis (CGN) is characterized by persistent inflammatory injury and progressive fibrotic remodeling, yet compound-target relationships underlying natural-product-based interventions remain incompletely defined. This study integrated network pharmacology, validated molecular docking, and in vitro experiments to evaluate candidate constituents of Cordyceps sinensis (C. sinensis) in CGN-related pathological processes. Candidate constituents of C. sinensis were screened, and the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform-derived compound-associated targets were intersected with CGN-associated genes. Functional enrichment and protein-protein interaction analyses were used to prioritize biological processes and hub targets. PTGS2 was identified as a key overlapping target. Molecular docking was performed using a celecoxib-bound COX-2 structure. Re-docking of the co-crystallized celecoxib ligand reproduced the crystallographic pose with an RMSD of 0.876 Å, supporting the docking protocol. β-Sitosterol and linoleyl acetate showed predicted compatibility with the COX-2 docking region, with binding affinities of -7.2 and -7.5 kcal/mol, respectively. β-Sitosterol was selected for compound-level validation in HBZY-1 rat glomerular mesangial cells. At 0.5-10 µM, β-sitosterol did not markedly reduce cell viability. In Lipopolysaccharide (LPS)-stimulated cells, β-sitosterol reduced Tnf, Il6, and Ptgs2 expression, decreased prostaglandin E2 (PGE2) production, and reduced cyclooxygenase-2 (COX-2) protein abundance. In transforming growth factor β1 (TGF-β1)-treated cells, β-sitosterol reduced Col1a1 and Acta2 expression and decreased alpha-smooth muscle actin (α-SMA) protein abundance. These findings provide hypothesis-generating evidence that β-sitosterol modulates inflammatory and profibrotic activation in mesangial-cell models, but they do not establish direct COX-2 enzymatic inhibition or therapeutic efficacy in CGN.
Hai-Peng He, Lian He, Fei Chen et al.· Journal of Visualized Experi...· 0 citations
Sarcopenia affects over 50 million individuals worldwide but lacks precision therapeutic strategies. The ADAMTSL3 rs4842838 (Val661Leu) variant may dysregulate TGF-β signaling and inflammatory responses in muscle wasting. This study aimed to establish an integrated computational-to-biological framework for identifying natural compounds (NCs) targeting inflammatory muscle wasting, using ADAMTSL3 rs4842838 (Val661Leu) variant-informed molecular docking and network pharmacology to prioritize candidate herbal extracts, which were subsequently validated in lipopolysaccharide (LPS)-induced C2C12 myotubes. Molecular docking of 25,000 NCs was performed against wild-type (WT) and mutant-type (MT) ADAMTSL3 Val661Leu structures. Compounds with binding energies ≤–9.5 kcal/mol were evaluated via network pharmacology. Biological validation used LPS-induced inflammatory muscle wasting in C2C12 myoblasts treated with gooseberry, licorice, and citrus peel extracts (1–125 µg/mL). Molecular clustering revealed superior performance for MT-selected NCs versus WT (silhouette score 0.75 vs. 0.63). MT-selected NCs required nitrogen-containing groups. Network pharmacology analysis identified licorice NCs targeting PDGFRB, AKT1, mTOR, and SOD1 pathways, while gooseberry NCs modulated matrix regulation via MMP3/MMP9. LPS treatment increased MMP3 expression by 51%; gooseberry and licorice extracts normalized MMP3 levels, while citrus peel extract showed partial recovery. All extracts upregulated muscle development genes (MYOG, MyoD1, ADAMTSL3), downregulated myostatin, reduced lipid peroxidation, and suppressed inflammatory markers (IL-1β, IL-6) (P < 0.05). The extracts enhanced TGF-β and insulin signaling while attenuating NF-κB activation, suggesting that the ADAMTSL3 rs4842838 variant disrupted TGF-β signaling and contributed to muscle wasting through dysregulated inflammatory responses. In conclusion, docking-informed network pharmacology analysis combined with in vitro validation supports a precision nutrition framework for inflammatory muscle wasting. Gooseberry, licorice, and citrus peel extracts exhibit multi-pathway muscle-protective effects through coordinated modulation of oxidative stress, inflammation, and TGF-β signaling.
Sunmi Park, Chen Li, H. Joe et al.· Applied Biological Chemistry· 0 citations
INTRODUCTION
Osteoarthritis (OA) is a prevalent and chronic joint disease characterized by progressive cartilage degeneration and chronic inflammation. Isoliquiritigenin (ISL), a bioactive flavonoid derived from licorice, has demonstrated significant anti-inflammatory potential in various diseases. However, its specific molecular targets and systemic mechanisms in the treatment of OA remain to be fully elucidated. This study aimed to investigate the potential targets and molecular mechanisms of ISL in OA treatment using an integrated pharmacological and experimental approach.
METHODS
Overlapping targets between ISL and OA were identified using multiple public databases. A PPI network was constructed to identify hub genes, followed by GO and KEGG enrichment analyses to predict key signaling pathways. A ceRNA regulatory network was also established. Furthermore, molecular docking was employed to assess the binding stability between ISL and core targets, and the findings were validated through histopathological evaluation (Mankin score) and RT-qPCR analysis in a rabbit ACLT-induced OA model.
RESULTS
A total of 79 shared targets were identified, from which 11 core targets were selected for further investigation. Enrichment analysis revealed that the therapeutic effects of ISL are primarily associated with the MAPK, PI3K-Akt, and mTOR signaling pathways, which are essential for maintaining chondrocyte homeostasis. Molecular docking indicated that ISL exhibits strong binding affinities (all binding energies < -5.0 kcal/mol) for the core targets. In vivo experiments confirmed typical cartilage degradation in the OA group, accompanied by significantly elevated Mankin scores. RT-qPCR results verified the significant differential expression of six core targets (IGF1R, PLAU, EGFR, PTGS2, PPARG, and GSK3B) in the OA cartilage, validating their involvement in OA pathogenesis.
DISCUSSION
In this study, we preliminarily determined the potential therapeutic effects of ISL on OA through its modulation of multiple targets and complex signaling pathways. The integration of network pharmacology and in vivo validation suggests that ISL may exert its anti-OA effects by targeting key inflammatory and metabolic mediators identified in our PPI and ceRNA networks.
CONCLUSION
ISL is predicted to have substantial potential for clinical application in OA treatment. These findings provide a novel theoretical foundation and specific candidate targets for future research into targeted therapeutic strategies for OA.
