代谢组学和综合网络药理学分析显示，复方消肿汤对非小细胞肺癌具有多靶点的抗癌作用

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-23 DOI:10.1016/j.phymed.2025.156855

Xinyuan Jiang , Zhiyong Xu , Huan Wang , Jiangnan Zhao , Nueraili Maihemuti , Sujing Jiang , Mingshu Xiao , Kaiyue Zhang , Sibei Liang , Yueli Shi , Kai Wang

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引用次数: 0

摘要

背景与目的非小细胞肺癌（NSCLC）是一种预后差、死亡率高的恶性肿瘤，在当代治疗中面临着重大挑战。这些挑战包括耐药性和副作用，这严重阻碍了当前治疗策略的有效性。越来越多的草药配方被用于抗肿瘤治疗，由于他们的成本效益，有益的功效，和额外的优势。扶正消积汤（FZXJD）是一种治疗肿瘤的方剂，已成功应用于非小细胞肺癌的临床治疗，但其作用机制尚不清楚。因此，本文综合运用网络药理学、代谢组学、生物学、分子对接等多种分析方法，阐明FZXJD对NSCLC的抑制机制。方法采用体外实验和肺癌异种移植模型，对复方泻精抗非小细胞肺癌（NSCLC）的疗效进行评价，并采用高效液相色谱法（HPLC）和网络药理学方法对复方泻精抑制NSCLC的主要成分和可能机制进行鉴定。随后，通过分子对接和生物学实验，探讨FZXJD及其主要效应成分齐墩果酸（OA）对NSCLC的抑制机制。最后，通过代谢组学和代谢物富集分析进一步研究FZXJD对肿瘤关键代谢途径的影响。结果体外实验证实了FZXJD对非小细胞肺癌的抑制作用。相应的，体内实验显示FZXJD抑制肿瘤进展，无明显毒副作用。网络药理学和分子对接发现，FZXJD参与抑制NSCLC的靶基因在PI3K/AKT和ERK/MAPK信号通路中显著富集。此外，还鉴定出14个核心基因（HSP90AA1、VEGFA、AKT1、JUN、EGFR、CASP3、ESR1、ERBB2、STAT3、MTOR、SRC、MDM2、CCND1、MAPK3）以及FZXJD抗肿瘤作用的主要成分OA。生物学实验和分子对接表明，FZXJD和OA通过抑制PI3K/AKT和ERK/MAPK两条重要通路发挥抗肿瘤作用。代谢组学分析表明，FZXJD治疗抑制体内谷胱甘肽代谢。结论fzxjd及其主要活性成分OA通过抑制PI3K/AKT和ERK/MAPK信号通路抑制NSCLC进展。FZXJD治疗也显著降低谷胱甘肽代谢。本研究为中药方剂在非小细胞肺癌中的应用提供了一种有前景的策略。

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Metabolomics and integrated network pharmacology analysis revealed multi-targeted anti-cancer effect of FuZhengXiaoJi decoction against non-small cell lung cancer

Background and purpose

As a malignant tumor characterized by a dismal prognosis and a high mortality rate, non-small cell lung cancer (NSCLC) presents significant challenges in contemporary treatment. These challenges include drug resistance and side effects, which severely hamper the effectiveness of current therapeutic strategies. An increasing number of herbal formulas have been utilized in antitumor therapy, owing to their cost-effectiveness, beneficial efficacy, and additional advantages. FuZhengXiaoJi Decoction (FZXJD), a cancer-treating formula, has been successfully applied in NSCLC clinical treatment, but the underlying mechanism remains elusive. Therefore, this paper integrated multiple analytical methods, including network pharmacology, metabolomics, biological approaches, and molecular docking to clarify how FZXJD suppresses NSCLC.

Methods

This study assessed the anti-NSCLC efficacy of FZXJD using in vitro assays and lung cancer xenograft models, and the primary components and potential mechanisms of FZXJD inhibition of NSCLC were identified by high-performance liquid chromatography (HPLC) and network pharmacology. Subsequently, inhibitory mechanisms of FZXJD and its principal effector component oleanolic acid (OA) on NSCLC were explored by molecular docking, as well as biological experiments. Finally, effects of FZXJD on critical metabolic pathways in tumors were further investigated by metabolomics and metabolite enrichment analysis.

Results

Inhibition of FZXJD on NSCLC cells was confirmed in vitro experiments. Correspondingly, in vivo experiments revealed that FZXJD impeded tumor progression without obvious toxic side effects. Network pharmacology and molecular docking disclosed that target genes involved in FZXJD’s inhibition of NSCLC were significantly enriched in the PI3K/AKT and ERK/MAPK signaling pathways. Additionally, 14 core genes (HSP90AA1, VEGFA, AKT1, JUN, EGFR, CASP3, ESR1, ERBB2, STAT3, MTOR, SRC, MDM2, CCND1, MAPK3) as well as the main component of the antitumor effect of FZXJD, the OA, were also identified. Biological experiments and molecular docking demonstrated that FZXJD and OA exerted antitumor effects by inhibiting two significant pathways, PI3K/AKT and ERK/MAPK. Metabolomics analysis indicated that FZXJD treatment suppressed glutathione metabolism in vivo.

Conclusion

FZXJD and its main active ingredient, OA, impede NSCLC progression by inhibiting PI3K/AKT and ERK/MAPK signaling pathways. FZXJD treatment also markedly attenuates glutathione metabolism. This research provides a promising strategy for the application of herbal formulas in NSCLC.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.