{"title":"基于非靶向代谢组学研究和网络药理学分析四君子汤通过m6A甲基转移酶METTL14抑制胃癌转移的机制","authors":"Xiangnan Li, Linlin Zhao, Jiluan Wang, Tianchi Ma, Jing Zhou, Yue Bian, Junfu Guo","doi":"10.2147/DDDT.S506702","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Sijunzi Decoction (SJZ), a Traditional Chinese Medicine (TCM) formula, is renowned for its capacity to fortify Qi and enhance spleen function. However, additional research is necessary to comprehend the mechanisms beneath the therapeutic potential of SJZ in gastric cancer.</p><p><strong>Objective: </strong>This research endeavored to analyze how SJZ treats gastric cancer using network pharmacology and experimental validation.</p><p><strong>Methods: </strong>Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and network pharmacology were applied to systemically clarify the mechanism of SJZ against gastric cancer. We used a xenograft tumor model of gastric cancer and gastric cancer cell lines to explore the effect of SJZ on N6-methyladenosine (m6A) modification. Cell transfection, plate clone formation, scratch migration, and transwell assays were performed in gastric cancer cell lines. The expression levels of m6A enzymes and epithelial-mesenchymal transition (EMT) markers were assessed by Quantitative real-time reverse transcription (RT-qPCR) and Western blotting.</p><p><strong>Results: </strong>The results revealed 511 active components and 196 targets of SJZ, with 167 targets associated with gastric cancer therapy. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis disclosed notable enrichment of pathways related to cancer, metabolism, and immunity. The protein-protein interaction (PPI) network comprised 274 nodes and 2902 edges, whereas the herbal component-target protein-pathway-disease network included 107 nodes and 345 edges, identifying four components with more than 20 putative targets. Experimental assays demonstrated a significant decrease in METTL3 expression following SJZ treatment, whereas the expression level of METTL14 was markedly elevated in the SJZ group across both gastric cancer cell lines and gastric cancer tissues derived from a mouse model (<i>P</i><0.01, <i>P</i><0.001, or <i>P</i><0.05). SJZ inhibited clone formation, migration, and invasion of gastric cancer cells, and EGFR and Vimentin expression via METTL14 (<i>P</i><0.05, <i>P</i><0.01, or <i>P</i><0.001).</p><p><strong>Conclusion: </strong>METTL14 appears integral to the inhibition of EMT by SJZ as a treatment for gastric cancer.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2369-2392"},"PeriodicalIF":4.7000,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970285/pdf/","citationCount":"0","resultStr":"{\"title\":\"The Mechanism of Sijunzi Decoction Suppresses Gastric Cancer Metastasis via the m6A Methyltransferase METTL14 Based on Untargeted Metabolomics Studies and Network Pharmacology Analysis.\",\"authors\":\"Xiangnan Li, Linlin Zhao, Jiluan Wang, Tianchi Ma, Jing Zhou, Yue Bian, Junfu Guo\",\"doi\":\"10.2147/DDDT.S506702\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Sijunzi Decoction (SJZ), a Traditional Chinese Medicine (TCM) formula, is renowned for its capacity to fortify Qi and enhance spleen function. However, additional research is necessary to comprehend the mechanisms beneath the therapeutic potential of SJZ in gastric cancer.</p><p><strong>Objective: </strong>This research endeavored to analyze how SJZ treats gastric cancer using network pharmacology and experimental validation.</p><p><strong>Methods: </strong>Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and network pharmacology were applied to systemically clarify the mechanism of SJZ against gastric cancer. We used a xenograft tumor model of gastric cancer and gastric cancer cell lines to explore the effect of SJZ on N6-methyladenosine (m6A) modification. Cell transfection, plate clone formation, scratch migration, and transwell assays were performed in gastric cancer cell lines. The expression levels of m6A enzymes and epithelial-mesenchymal transition (EMT) markers were assessed by Quantitative real-time reverse transcription (RT-qPCR) and Western blotting.</p><p><strong>Results: </strong>The results revealed 511 active components and 196 targets of SJZ, with 167 targets associated with gastric cancer therapy. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis disclosed notable enrichment of pathways related to cancer, metabolism, and immunity. The protein-protein interaction (PPI) network comprised 274 nodes and 2902 edges, whereas the herbal component-target protein-pathway-disease network included 107 nodes and 345 edges, identifying four components with more than 20 putative targets. Experimental assays demonstrated a significant decrease in METTL3 expression following SJZ treatment, whereas the expression level of METTL14 was markedly elevated in the SJZ group across both gastric cancer cell lines and gastric cancer tissues derived from a mouse model (<i>P</i><0.01, <i>P</i><0.001, or <i>P</i><0.05). SJZ inhibited clone formation, migration, and invasion of gastric cancer cells, and EGFR and Vimentin expression via METTL14 (<i>P</i><0.05, <i>P</i><0.01, or <i>P</i><0.001).</p><p><strong>Conclusion: </strong>METTL14 appears integral to the inhibition of EMT by SJZ as a treatment for gastric cancer.</p>\",\"PeriodicalId\":11290,\"journal\":{\"name\":\"Drug Design, Development and Therapy\",\"volume\":\"19 \",\"pages\":\"2369-2392\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-03-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970285/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug Design, Development and Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2147/DDDT.S506702\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Design, Development and Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2147/DDDT.S506702","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
The Mechanism of Sijunzi Decoction Suppresses Gastric Cancer Metastasis via the m6A Methyltransferase METTL14 Based on Untargeted Metabolomics Studies and Network Pharmacology Analysis.
Background: Sijunzi Decoction (SJZ), a Traditional Chinese Medicine (TCM) formula, is renowned for its capacity to fortify Qi and enhance spleen function. However, additional research is necessary to comprehend the mechanisms beneath the therapeutic potential of SJZ in gastric cancer.
Objective: This research endeavored to analyze how SJZ treats gastric cancer using network pharmacology and experimental validation.
Methods: Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and network pharmacology were applied to systemically clarify the mechanism of SJZ against gastric cancer. We used a xenograft tumor model of gastric cancer and gastric cancer cell lines to explore the effect of SJZ on N6-methyladenosine (m6A) modification. Cell transfection, plate clone formation, scratch migration, and transwell assays were performed in gastric cancer cell lines. The expression levels of m6A enzymes and epithelial-mesenchymal transition (EMT) markers were assessed by Quantitative real-time reverse transcription (RT-qPCR) and Western blotting.
Results: The results revealed 511 active components and 196 targets of SJZ, with 167 targets associated with gastric cancer therapy. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis disclosed notable enrichment of pathways related to cancer, metabolism, and immunity. The protein-protein interaction (PPI) network comprised 274 nodes and 2902 edges, whereas the herbal component-target protein-pathway-disease network included 107 nodes and 345 edges, identifying four components with more than 20 putative targets. Experimental assays demonstrated a significant decrease in METTL3 expression following SJZ treatment, whereas the expression level of METTL14 was markedly elevated in the SJZ group across both gastric cancer cell lines and gastric cancer tissues derived from a mouse model (P<0.01, P<0.001, or P<0.05). SJZ inhibited clone formation, migration, and invasion of gastric cancer cells, and EGFR and Vimentin expression via METTL14 (P<0.05, P<0.01, or P<0.001).
Conclusion: METTL14 appears integral to the inhibition of EMT by SJZ as a treatment for gastric cancer.
期刊介绍：
Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications.
The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas.
Specific topics covered by the journal include:
Drug target identification and validation
Phenotypic screening and target deconvolution
Biochemical analyses of drug targets and their pathways
New methods or relevant applications in molecular/drug design and computer-aided drug discovery*
Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes)
Structural or molecular biological studies elucidating molecular recognition processes
Fragment-based drug discovery
Pharmaceutical/red biotechnology
Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products**
Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development
Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing)
Preclinical development studies
Translational animal models
Mechanisms of action and signalling pathways
Toxicology
Gene therapy, cell therapy and immunotherapy
Personalized medicine and pharmacogenomics
Clinical drug evaluation
Patient safety and sustained use of medicines.
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