Integrative network pharmacology, transcriptomics, and proteomics reveal the material basis and mechanism of the Shen Qing Weichang Formula against gastric cancerWang, Sun, Ren
et alChin Med (2025) 20 (1), 42
Abstract: Gastric cancer (GC) is a common malignancy with poor prognosis and lack of efficient therapeutic methods. Shen Qing Weichang Formula (SQWCF) is a patented traditional herbal prescription for GC, but its efficacy and underlying mechanism remains to be clarified.To explore the efficacy and potential mechanism of SQWCF in treating GC.A subcutaneous transplantation tumor model of human GC was established for assessing SQWCF's efficacy and safety. A comprehensive strategy integrating mass spectrometry, network pharmacology, omics analysis, and bioinformatic methods was adopted to explore the core components, key targets, and potential mechanism of SQWCF in treating GC. Molecular docking, immunohistochemistry, quantitative real-time PCR, and western blot were applied to validation.In the mouse model of GC, SQWCF effectively suppressed the GC growth without evident toxicity and enhanced the therapeutic efficacy of paclitaxel. Network pharmacology and molecular docking based on mass spectrometry showed that key targets (CASP3, TP53, Bcl-2, and AKT1) and core active components (Calycosin, Glycitein, Liquiritigenin, Hesperetin, and Eriodictyol) involved in the anti-GC effect of SQWCF had stable binding affinity, of which AKT1 ranked the top in the affinity. Validation based on network pharmacology and omics analysis confirmed that PI3K-AKT and MAPK signaling pathways, as well as downstream apoptosis pathway, explained the therapeutic effects of SQWCF on GC. In addition, family with sequence similarity 81 member A (FAM81A) was identified as a novel biomarker of GC that was aberrantly highly expressed in GC and associated with poor prognosis by bioinformatic analysis, and was an effector target of SQWCF at both mRNA and protein levels.This study uncovers a synergistic multi-component, multi-target, and multi-pathway regulatory mechanism of SQWCF in treating GC comprehensively, emphasizing its potential for therapeutic use and providing new insights into GC treatment.© 2025. The Author(s).
Comprehensive Molecular and Genomic Analysis of NCI-MATCH Subprotocol Y: Capivasertib in Patients With an AKT1 E17K-Mutated TumorMcCourt, Gross, Kalinsky
et alJCO Precis Oncol (2025) 9, e2400614
Abstract: NCI-MATCH (EAY131) is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatments. Arm Y evaluated capivasertib, a pan AKT inhibitor, in patients with an AKT1 E17K-mutated tumor. Here, we report on the translational objectives of the study, a molecular and genomic analysis of specimens to identify potential biomarkers of response or resistance to capivasertib.Eligible patients had AKT1 E17K-mutated metastatic tumors that progressed with standard treatment and received capivasertib 480 mg orally twice daily for 4 days on and 3 days off weekly in 28-day cycles. The primary end point was objective response rate (ORR). We performed whole-exome sequencing, RNA sequencing, and gene set and pathway enrichment analysis on 25 pretreatment tissue samples and evaluated findings in responders (complete response [CR], n = 0, and partial response, n = 9) and nonresponders (stable disease, n = 13, and progressive disease, n = 3).The ORR was 28.6% (10 of 35) in the reported primary trial and 36% (9 of 25) in this translational cohort. Mutations in the TP53 gene were more frequent in responders, whereas the PI3K/AKT/mTOR pathway genes TYRO3, SYNJ1, and CDIPT were significantly altered in nonresponders. DNA repair, p53, E2F, and Wnt-beta catenin pathways were enriched in the responder group. Unsupervised clustering of gene expression identified five genes, ANKRD30A, SUSD4, TTC6, POTEJ, and POTEI, that were significantly higher in responders and lower in nonresponders. In addition, EGFR expression was significantly increased in nonresponders.In patients with AKT1 E17K-mutated tumors, capivasertib achieved a clinically significant ORR. TP53 mutations appear to be associated with response, whereas certain additional PI3K/AKT/mTOR pathway mutations and EGFR overexpression appear to be associated with nonresponse to capivasertib. Further investigation of predictive biomarkers is warranted.
Exploring the mechanism of Epimedium in treating diabetic nephropathy based on network pharmacology and experimental validation studyHuang, Li, Han
Cytotechnology (2025) 77 (3), 82
Abstract: Diabetic nephropathy (DN) is a severe complication of diabetes, characterized by chronic inflammation, metabolic disturbances, and progressive renal damage. Natural perennial herb, such as Epimedium, has shown potential therapeutic effects on DN, but its underlying mechanisms remain unclear. This study aimed to explore the pharmacological mechanisms of Epimedium in the treatment of DN through network pharmacology, molecular docking, and experimental validation. Active components of Epimedium were identified using TCMSP and SwissTargetPrediction databases, while DN-related targets were retrieved from GeneCards, DisGeNET, OMIM, and TTD databases. Overlapping targets were analyzed via PPI network and Cytoscape's cytoHubba plugin to identify hub genes. GO and KEGG enrichment analyses were conducted to explore functional pathways. Molecular docking validated the binding affinity between key targets and active components. Finally, high-glucose-induced HK-2 cell injury models were used to verify the protective effects of Epimedium through RT-qPCR, western blotting, and mitochondrial function assays. A total of 224 overlapping targets were identified, with AKT1, TNF, HSP90AA1, and SRC serving as key hub genes. GO and KEGG analyses revealed significant enrichment in pathways such as the PI3K-Akt signaling pathway and lipid metabolism. Molecular docking demonstrated strong interactions between Epimedium components and hub targets. Experimental validation showed that Epimedium restored nephrin and WT1 protein levels, mitigated mitochondrial dysfunction, and reversed high-glucose-induced overexpression of key targets. Epimedium exerts therapeutic effects on DN through multi-target interactions, primarily via the PI3K-Akt pathway, highlighting its potential as a novel treatment for DN.The online version contains supplementary material available at 10.1007/s10616-025-00748-0.© The Author(s), under exclusive licence to Springer Nature B.V. 2025. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
Integrating network pharmacology and experimental validation to uncover the synergistic effects of Huangqi ()-Ezhu () with 5-fluorouracil in colorectal cancer modelsXiying, Ruxin, Jing
et alJ Tradit Chin Med (2025) 45 (2), 385-398
Abstract: To evaluate the effects of Huangqi (Radix Astragali Mongolici)-Ezhu (Rhizoma Curcumae Phaeocaulis) (HQEZ) on colorectal cancer therapies and to elucidate the potential mechanisms of HQEZ, especially in combination with 5-Fluorouracil (5-FU).The anti-tumor effects of HQEZ were evaluated in colorectal cancer models both in vivo and in vitro. The network pharmacological assay was used to investigate potential mechanisms of HQEZ. Potential target genes were selected by Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, protein-protein interaction network (PPI) and molecular docking. Within key targets, potential targets related to drug sensitivity, especially the sensitivity to 5-FU, were evaluated in HCT116 in vitro by immunofluorescence, quantitative real-time polymerase chain reaction (qPCR) and Western-blot. Then, changes in potential targets were assessed in tumors from tumor-bearing mice and the expression of these targets was also evaluated in colorectal cancer (COAD) patients from the Cancer Genome Atlas Program (TCGA) database.HQEZ significantly enhanced the anti-tumor activity of 5-FU in vivo and inhibit the growth of HCT116 in vitro. By network pharmacological analysis, key targets, such as protein kinase B (AKT1), epidermal growth factor receptor (EGFR), adenosine triphosphate (ATP) binding cassette subfamily B member 1 (ABCB1, also named multidrug resistance protein 1, MDR1), ATP binding cassette subfamily G member 2 (ABCG2), thymidylate synthetase (TYMS, also named TS), prostaglandin-endoperoxide synthase 2 (PTGS2), matrix metallopeptidase 2 (MMP2), MMP9, toll like receptor 4 (TLR4), TLR9 and dihydropyrimidine dehydrogenase (DPYD), were identified. Additionally, 4 potential core active ingredients (Folate, Curcumin, quercetin and kaempferol) were identified to be important for the treatment of colorectal cancer with HQEZ. In key targets, chemoresistance related targets were validated to be affected by HQEZ. Furthermore, 5-FU sensitivity related targets, including MDR1, TS, EGFR, ribonucleotide reductase catalytic subunit M1, Breast and Ovarian Cancer Susceptibility Protein 1 (BRCA1) and mutl homolog 1 were also significantly reduced by HQEZ both in vitro and in vivo. Finally, these validated key targets and 5-FU sensitivity related targets were demonstrated to be up-regulated in COAD patients based on TCGA database.HQEZ has synergistic effects on the anti-tumor activity of 5-FU in the treatment of colorectal cancer both in vivo and in vitro. The beneficial effect of HQEZ results from the inhibition of the drug sensitivity targets associated with 5-FU. The combination therapy of HQEZ with 5-FU or other chemotherapeutic drugs will also improve the anti-tumor efficacy of chemotherapy.
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