探索4-羟基苯甲酸甲酯相关的CDK1失调在乳腺癌中的作用：一项结合网络毒理学、转录组学和分子动力学的多组学研究
Exploring Methyl-4-hydroxybenzoate-associated CDK1 dysregulation in breast cancer: A multi-omics investigation combining network toxicology, transcriptomics, and molecular dynamics.
摘要(中文译文)
乳腺癌仍是全球重大健康负担，环境内分泌干扰化学物可能参与乳腺癌相关表型的发生。对羟基苯甲酸甲酯（MEP；尼泊金甲酯）是一种广泛使用的防腐剂，据报道具有弱雌激素活性，但其与乳腺癌的分子关联尚未完全明确。本研究采用整合性探索框架，结合靶点预测、乳腺癌表达数据集、蛋白质-蛋白质相互作用分析、功能富集、单细胞转录组特征分析、分子对接、分子动力学模拟及体外实验。靶点预测识别出1067个推定的MEP相关候选靶点。与乳腺癌相关基因集及GEO来源的差异表达基因整合后，获得29个共享基因，其中EGFR、TYMS、EZH2、CDK1和BIRC5成为高度连接的网络节点。富集分析提示细胞周期相关及癌症相关通路。单细胞分析经修订后描述为MEP靶点特征高表达和低表达细胞群，而非直接检测MEP转录本。对接和分子动力学分析提示所选MEP-蛋白质复合物具有潜在结合能力和结构稳定性；然而，这些计算数据被解释为推定关联的证据，而非直接的激酶激活。体外实验和转录组分析提示，MEP暴露与增殖相关表型及细胞周期转录程序的改变相关。总体而言，这些发现支持一个产生假说的模型，即MEP与乳腺癌相关的转录和信号改变相关，但仍需进一步的直接机制验证，包括CDK1活性、功能缺失、挽救实验及体内研究。
Abstract
Breast cancer remains a major global health burden, and environmental endocrine-disrupting chemicals may contribute to breast-cancer-related phenotypes. Methyl-4-hydroxybenzoate (MEP; methylparaben) is a widely used preservative with reported weak estrogenic activity, but its molecular association with breast cancer remains incompletely defined. In this study, we used an integrative exploratory framework combining target prediction, breast-cancer expression datasets, protein-protein interaction analysis, functional enrichment, single-cell transcriptomic signature analysis, molecular docking, molecular dynamics simulation, and in vitro assays. Target prediction identified 1067 putative MEP-associated candidates. Integration with breast-cancer-associated gene sets and GEO-derived differentially expressed genes yielded 29 shared genes, from which EGFR, TYMS, EZH2, CDK1, and BIRC5 emerged as highly connected network nodes. Enrichment analyses implicated cell-cycle-related and cancer-associated pathways. Single-cell analyses were revised to describe MEP-target-signature-high and MEP-target-signature-low cell groups rather than direct measurement of MEP as a transcript. Docking and molecular dynamics analyses suggested potential binding and structural stability for selected MEP-protein complexes; however, these computational data were interpreted as evidence of putative association rather than direct kinase activation. In vitro assays and transcriptomic profiling suggested that MEP exposure was associated with altered proliferation-related phenotypes and cell-cycle transcriptional programs. Overall, the findings support a hypothesis-generating model in which MEP is associated with breast-cancer-relevant transcriptional and signaling alterations, while further direct mechanistic validation, including CDK1 activity, loss-of-function, rescue, and in vivo studies, is required.
如何引用
AMA
Yang Wang, Jing Li, Zhen Liu, Yanhong Ding, Hongmei Li. Exploring Methyl-4-hydroxybenzoate-associated CDK1 dysregulation in breast cancer: A multi-omics investigation combining network toxicology, transcriptomics, and molecular dynamics.. Biochemical and biophysical research communications. 2026; doi:10.1016/j.bbrc.2026.154295.
APA
Yang Wang, Jing Li, Zhen Liu, Yanhong Ding, Hongmei Li (2026). Exploring Methyl-4-hydroxybenzoate-associated CDK1 dysregulation in breast cancer: A multi-omics investigation combining network toxicology, transcriptomics, and molecular dynamics.. Biochemical and biophysical research communications. https://doi.org/10.1016/j.bbrc.2026.154295
GB/T 7714
Yang Wang, Jing Li, Zhen Liu, Yanhong Ding, Hongmei Li. Exploring Methyl-4-hydroxybenzoate-associated CDK1 dysregulation in breast cancer: A multi-omics investigation combining network toxicology, transcriptomics, and molecular dynamics.[J]. Biochemical and biophysical research communications, 2026 doi:10.1016/j.bbrc.2026.154295.
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