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Results for “Multi-target synergistic regulation”

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PubMed2026

Sanguinarine as a multi-target therapeutic candidate for laryngeal cancer: insights from network pharmacology, molecular dynamics and in vitro validation.

OBJECTIVE: To identify the core targets and elucidate the potential molecular mechanisms of sanguinarine (SA) against laryngeal squamous cell carcinoma (LSCC), and to validate its antitumor effects in vitro. METHODS: Potential targets of SA were predicted using SwissTargetPrediction, TargetNet, and SuperPred and intersected with LSCC-related targets obtained from the GeneCards, OMIM, and DISEASES databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. A protein-protein interaction (PPI) network was constructed using the STRING database (combined score > 0.900), and topological parameters including degree centrality (DC), betweenness centrality (BC), closeness centrality (CC), eigenvector centrality (EC), and local average connectivity (LAC) were calculated in Cytoscape to identify core genes based on median thresholds. Molecular docking and 100-ns molecular dynamics (MD) simulations were conducted for epidermal growth factor receptor (EGFR), Phosphatidylinositide-3-kinase catalytic subunit alpha (PIK3CA), phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit β (PIK3CB), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD), and Non-Receptor Tyrosine Kinase (SRC). The effects of SA on LSCC were evaluated using CCK-8, colony formation, Transwell migration, and wound-healing assays in TU177 cells and TU212. RESULTS: A total of 213 common targets were identified, which were significantly enriched in PI3K-Akt signaling, EGFR tyrosine kinase inhibitor resistance, and adhesion- and migration-related pathways. The PPI network comprised 259 nodes and 259 edges, from which five core genes-PIK3CA, PIK3CB, PIK3CD, EGFR, and SRC-were identified. Molecular docking revealed strong binding affinities between SA and the PI3K family proteins (- 9.79 to - 10.96 kcal/mol), as well as EGFR (- 8.58 kcal/mol) and SRC (- 6.77 kcal/mol). MD simulations indicated greater stability of SA complexes with EGFR and PI3K family members compared with SRC. In vitro assays demonstrated that SA significantly inhibited TU177 cell and TU212 cell proliferation, colony formation, and migration. CONCLUSION: SA may exert anti-laryngeal cancer effects through synergistic multi-target inhibition centered on the EGFR/SRC/PI3K signaling axis, highlighting its potential as a promising therapeutic candidate for LSCC.

Humans↗

PubMed2026

Integrative computational analysis combining network pharmacology, regulatory network modeling, and molecular dynamics reveals the mechanisms of Quanshen compound in ITP.

UNLABELLED: Immune thrombocytopenia (ITP) is a hemorrhagic disorder caused by immune dysfunction. Quanshen Compound (QSC) is an in-house preparation developed by the Uyghur Hospital in Hotan Prefecture. This study primarily investigates and validates the potential pharmacological basis and mechanism of action of QSC in modulating immune thrombopoiesis. Based on the multi-database screening of the QSC and the related targets of ITP, the intersection was obtained to construct a protein-protein interaction (PPI) network and screen the core targets; the intersection targets were analyzed for gene ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using R packages; a component-target-pathway network was constructed to screen the key active components and their mechanisms of action. At the same time, the TF-mRNA-miRNA regulatory network of the core targets was constructed, and chromosome localization and subcellular localization analysis were performed; further, the binding stability of key components and core targets was verified through molecular docking and molecular dynamics simulation. A total of 227 potential target sites were screened out, among which TNF, IL6, AKT1, TP53 and IL1B were the core targets. The enrichment results indicated that these intersecting target sites mainly participated in inflammatory responses, immune regulation and hemostasis-related biological processes, and were significantly enriched in the PI3K-Akt signaling pathway, Toll-like receptor signaling pathway, Th17 cell differentiation and PD-1/PD-L1 signaling pathway. The core target TF-mRNA-miRNA regulatory network contained 184 nodes and 200 edges, suggesting that the core targets were subject to multi-level regulation. Molecular docking results showed that the main active components had good binding activity with the core targets, and molecular dynamics simulation further verified the stability of the complex. QSC may improve ITP through a multi-component, multi-target, and multi-pathway synergistic mechanism involving key targets such as TNF, IL6, AKT1, TP53, and IL1B, as well as the PI3K-Akt signaling pathway. These findings provide new insights into the potential therapeutic mechanisms of QSC against ITP and warrant further experimental validation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00718-0.

Immune thrombocytopenia↗

PubMed2026

[Study on mechanism of Wendan Decoction in intervening in nonalcoholic fatty liver disease based on proteomics and network pharmacology].

This study systematically explored the molecular mechanism of Wendan Decoction(WDD) in treating nonalcoholic fatty liver disease(NAFLD) by integrating network pharmacology, proteomics, and experimental validation. A mouse NAFLD model was established using a high-fat diet, and the mice were randomly divided into a blank control group, a model group, a positive drug group(simvastatin, 3.03 mg·kg~(-1)), and low-(3.035 g·kg~(-1)), medium-(6.07 g·kg~(-1)), and high-dose(12.14 g·kg~(-1)) WDD groups, with intervention lasting for 6 weeks. After the intervention, the serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), triglycerides(TG), total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C), and high-density lipoprotein cholesterol(HDL-C) were measured using an automatic biochemical analyzer. The serum levels of interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) were detected by ELISA. Liver histopathology was observed via hematoxylin-eosin(HE) staining and oil red O staining. Network pharmacology was used to predict potential targets and pathways, and proteomics was applied to identify differentially expressed proteins and related pathways. RT-qPCR and Western blot were performed to detect mRNA and protein expression of relevant genes. Animal experiments demonstrated that WDD dose-dependently ameliorated hepatic steatosis, inflammation, and lipid deposition, significantly reducing serum levels of ALT, AST, TG, TC, LDL-C, and pro-inflammatory cytokines(IL-1β, IL-6, and TNF-α), while significantly increasing serum HDL-C levels. Network pharmacology screening identified naringenin, baicalein, and other key active components, which were involved in pathways such as the peroxisome proliferator-activated receptor(PPAR), lipid, and atherosclerosis pathways. Proteomics further revealed differentially expressed pathways including the PPAR and advanced glycation end product-receptor(AGE-RAGE) signaling pathways. Integrated analysis highlighted the PPAR signaling pathway as the core mechanism. Molecular biology validation showed that WDD significantly regulated the mRNA expression of sterol regulatory element-binding protein-1c(SREBP-1c), fatty acid synthase(FASN), carnitine palmitoyl transferase 1A(CPT1A), acyl-CoA oxidase 1(ACOX1), and PPARα, as well as protein expression of PPARα, CPT1A, and PPARγ in mouse liver tissue. These results suggested that WDD might exert a multi-component, multi-target, and multi-pathway synergistic effect to improve lipid metabolism disorders and inflammatory responses with the PPAR signaling pathway as the central hub, thereby alleviating NAFLD progression.

Animals↗

PubMed2026

Exploring the Potential Molecular Targets of Cyanidin-3-O-glucoside for Type 2 Diabetes Mellitus Treatment.

INTRODUCTION: This study aims to elucidate the multi-target molecular mechanism of cyanidin-3-O-glucoside (C3G) in treating Type 2 Diabetes (T2DM) through network pharmacology methods. METHODS: The study was designed to predict the targets of C3G through public databases and to screen for T2DM-related targets. Protein-protein interaction (PPI) network analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on the common targets. Core targets were further validated through molecular docking and molecular dynamics (MD) simulations. RESULTS: This research identified a total of 57 potential targets of C3G in the treatment of T2DM. Subsequent PPI analysis identified ALB (Degree=43), AKT1 (Degree=41), and TNF (Degree=41) as the top three hub proteins. Pathway analysis indicated significant involvement in the insulin signaling pathway (P = 4.205×10-9), AMPK signaling pathway (P = 9.582×10-7), and FoxO signaling pathway (P = 1.315×10-6). Molecular docking revealed strong binding affinities between C3G and NOS3 (-9.5 kcal/mol), PPARG (-9.0 kcal/mol), TNF (-8.5 kcal/mol), and INSR (-8.4 kcal/mol). MD simulations further confirmed that the C3G-target complex has excellent binding stability. DISCUSSION: C3G may intervene in the pathological progression of T2DM by regulating key pathways such as insulin sensitivity, inflammatory responses, and oxidative stress. Further studies suggest that INSR and NOS3 may be new targets through which C3G exerts its effects, but their specific mechanisms and in vivo biological functions still need to be elucidated by subsequent experiments. CONCLUSION: C3G may intervene in the progression of T2DM in a multi-pathway synergistic manner by targeting key molecules such as INSR and NOS3.

Anthocyanins↗