通过网络药理学、分子对接和分子动力学模拟探索葫芦素B在肝细胞癌中的抗肿瘤潜力。
Exploring the antitumor potential of cucurbitacin B in hepatocellular carcinoma through network pharmacology, molecular docking, and molecular dynamics simulations.
作者信息
Zhang Hongyu, Wu Baixiu, Ke Liuhua, Fan Xiaoyuan, Huang Liji, Peng Zheng
机构信息
Department of Clinical Laboratory, Third Affiliated Hospital of Guangxi University of Chinese Medicine, Liuzhou Traditional Chinese Medical Hospital, Third Clinical Faculty of Guangxi University of Chinese Medicine, 6 Honghu Road, Liuzhou, 545000, Guangxi, China.
Department of Gynecology, Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou Worker's Hospital, Liuzhou, Guangxi, China.
出版信息
Naunyn Schmiedebergs Arch Pharmacol. 2025 May 21. doi: 10.1007/s00210-025-04273-x.
Cucurbitacin B exhibits promising anticancer activity across various cancers; however, its precise mechanism remains unclear. This study integrates network pharmacology, molecular docking, and dynamics simulations to elucidate CuB's multitarget therapeutic mechanisms against HCC. Potential CuB targets were retrieved from CTD, HERB, SwissTargetPrediction, ETCM, and PharmMapper databases. HCC-related genes were sourced from GEO datasets (GSE216613, GSE101685, GSE62232, GSE46408), GeneCard, DisGeNET, OMIM, and TTD. Intersecting targets were analyzed via PPI networks (STRING/Cytoscape), followed by GO/KEGG enrichment (DAVID). Molecular docking (Autodock Vina), ADMET evaluation (ADMETlab 2.0), and molecular dynamics simulations (Amber20) validated interactions. Core targets were further verified using GEPIA, HPA, cBioPortal, and TIMER databases. A total of 139 shared targets were identified between CuB and HCC. Key targets included EGFR, MTOR, MMP9, HSP90AB1, STAT3, and TNF. KEGG pathway analysis revealed significant enrichment in the phosphatidylinositol 3-kinase/protein kinase B (PI3K-Akt) signaling pathway, alongside cancer-related pathways (e.g., lipid metabolism, EGFR tyrosine kinase inhibitor resistance). Molecular docking confirmed strong binding (energy < - 5.0 kcal/mol) between CuB and core targets (e.g., MTOR: - 8.2 kcal/mol; HSP90AB1: - 7.9 kcal/mol). ADMET profiling indicated favorable pharmacokinetic properties, and molecular dynamics simulations demonstrated stable ligand-receptor complexes (RMSD < 2.5 Å). External validation highlighted differential expression (HSP90AB1, TNF) and clinical correlations (CCND1, EGFR) in HCC. CuB exerts antitumor effects in HCC through multitarget modulation, primarily via PI3K-Akt signaling and interactions with EGFR, MTOR, and HSP90AB1. This study provides a mechanistic foundation for CuB's therapeutic potential in HCC, guiding future experimental and clinical investigations.
葫芦素B在多种癌症中展现出有前景的抗癌活性；然而，其确切机制仍不清楚。本研究整合网络药理学、分子对接和动力学模拟，以阐明葫芦素B针对肝癌的多靶点治疗机制。从CTD、HERB、SwissTargetPrediction、ETCM和PharmMapper数据库中检索潜在的葫芦素B靶点。肝癌相关基因来源于GEO数据集（GSE216613、GSE101685、GSE62232、GSE46408）、基因卡片、DisGeNET、OMIM和TTD。通过蛋白质-蛋白质相互作用网络（STRING/Cytoscape）分析交集靶点，随后进行基因本体论/京都基因与基因组百科全书富集分析（DAVID）。分子对接（Autodock Vina）、药物代谢及药物相互作用预测评估（ADMETlab 2.0）和分子动力学模拟（Amber20）验证相互作用。使用GEPIA、人类蛋白质图谱（HPA）、cBioPortal和TIMER数据库进一步验证核心靶点。在葫芦素B和肝癌之间共鉴定出139个共享靶点。关键靶点包括表皮生长因子受体（EGFR）、雷帕霉素靶蛋白（MTOR）、基质金属蛋白酶9（MMP9）、热休克蛋白90α家族成员1（HSP90AB1）、信号转导和转录激活因子3（STAT3）和肿瘤坏死因子（TNF）。京都基因与基因组百科全书通路分析显示，磷脂酰肌醇3-激酶/蛋白激酶B（PI3K-Akt）信号通路以及与癌症相关的通路（如脂质代谢、EGFR酪氨酸激酶抑制剂耐药性）有显著富集。分子对接证实葫芦素B与核心靶点之间有强结合（能量< -5.0千卡/摩尔）（例如，MTOR：-8.2千卡/摩尔；HSP90AB1：-7.9千卡/摩尔）。药物代谢及药物相互作用预测分析表明其具有良好的药代动力学性质，分子动力学模拟证明配体-受体复合物稳定（均方根偏差<2.5埃）。外部验证突出了肝癌中（HSP90AB1、TNF）的差异表达以及（细胞周期蛋白D1、EGFR）的临床相关性。葫芦素B通过多靶点调节在肝癌中发挥抗肿瘤作用，主要通过PI3K-Akt信号通路以及与EGFR、MTOR和HSP90AB1的相互作用。本研究为葫芦素B在肝癌治疗中的潜在应用提供了机制基础，指导未来的实验和临床研究。
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