The Mechanism of Sijunzi Decoction Suppresses Gastric Cancer Metastasis via the m6A Methyltransferase METTL14 Based on Untargeted Metabolomics Studies and Network Pharmacology Analysis.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-03-31 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S506702

Xiangnan Li, Linlin Zhao, Jiluan Wang, Tianchi Ma, Jing Zhou, Yue Bian, Junfu Guo

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引用次数: 0

Abstract

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.

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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

背景：四君子汤（SJZ）是一种传统的中药配方，以其健气和健脾的能力而闻名。然而，需要进一步的研究来了解SJZ在胃癌治疗潜力下的机制。目的：利用网络药理学和实验验证的方法分析SJZ治疗胃癌的疗效。方法：采用液相色谱-串联质谱联用（LC-MS/MS）和网络药理学方法，系统阐明参参参抗胃癌的作用机制。我们采用胃癌异种移植瘤模型和胃癌细胞系，探讨SJZ对n6 -甲基腺苷（m6A）修饰的影响。对胃癌细胞系进行了细胞转染、平板克隆形成、划痕迁移和transwell实验。定量实时反转录（RT-qPCR）和Western blotting检测m6A酶和上皮间质转化（EMT）标志物的表达水平。结果：发现SJZ有效成分511个，靶点196个，其中167个靶点与胃癌治疗相关。京都基因与基因组百科全书（KEGG）富集分析显示，与癌症、代谢和免疫相关的途径显著富集。蛋白质-蛋白质相互作用（PPI）网络包括274个节点和2902条边，而草药成分-靶点蛋白-途径-疾病网络包括107个节点和345条边，确定了4个成分有超过20个推测靶点。实验分析表明，在SJZ治疗后，METTL3的表达显著降低，而METTL14的表达水平在SJZ组的胃癌细胞系和小鼠模型衍生的胃癌组织中均显着升高（ppppppp）。结论：METTL14似乎是SJZ抑制EMT作为胃癌治疗的一部分。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

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.