Gong Hong, Li Jiayu, Pu Rong, Huang Jian
Department of Traditional Chinese Medicine, The Affiliated Hospital of Yunnan University, 176 Qingnian Road, Kunming, Yunnan 650200, China.
School of Health Sciences, Dehong Vocational College, 11 Yingshui Road, Mangshi, Dehong Prefecture, Yunnan 678400, China.
Toxicol Res (Camb). 2025 Aug 6;14(4):tfaf113. doi: 10.1093/toxres/tfaf113. eCollection 2025 Aug.
The pathogenesis of Alzheimer's disease remains incompletely understood. Methyl-4-hydroxybenzoic acid, a common chemical additive, may play a role, though its mechanisms are unclear. This research investigated the potential causal link between Methyl-4-hydroxybenzoic acid and Alzheimer's disease and examined underlying molecular mechanisms. Mendelian randomization analysis evaluated causality, using Cochran's Q test, the Mendelian Randomization-Egger intercept test, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier to assess heterogeneity and sensitivity. Methyl-4-hydroxybenzoic acid targets were identified through multiple databases, and a related target library was constructed using Weighted Gene Co-expression Network Analysis, differential gene expression analysis, and the Genecards database. A Protein-Protein Interaction network identified core genes, validated by molecular docking. Transcriptomic analysis and single-cell expression data explored cell-type-specific expression patterns. Results showed a significant positive causal association between Methyl-4-hydroxybenzoic acid and Alzheimer's disease. We identified 198 Methyl-4-hydroxybenzoic acid targets, with 99 genes associated with both Methyl-4-hydroxybenzoic acid and Alzheimer's disease. Six core genes (EGFR, ESR1, MAPK3, MMP9, PTGS2, TP53) were pinpointed. Functional enrichment implicated neuronal signaling, inflammation, and metabolism. Multi-omics and single-cell analyses revealed differential expression of core genes in key brain regions. Molecular docking confirmed stable interactions between Methyl-4-hydroxybenzoic acid and these proteins. This research confirms a causal relationship between Methyl-4-hydroxybenzoic acid and Alzheimer's disease, revealing potential molecular mechanisms and core gene functions, offering insights into pathogenesis and therapeutic targets.
阿尔茨海默病的发病机制仍未完全明确。甲基-4-羟基苯甲酸作为一种常见的化学添加剂，可能在其中发挥作用，但其机制尚不清楚。本研究调查了甲基-4-羟基苯甲酸与阿尔茨海默病之间潜在的因果关系，并探究了其潜在的分子机制。孟德尔随机化分析采用Cochran's Q检验、孟德尔随机化Egger截距检验以及孟德尔随机化多效性残差和离群值检验来评估异质性和敏感性，以此评估因果关系。通过多个数据库鉴定甲基-4-羟基苯甲酸的靶点，并利用加权基因共表达网络分析、差异基因表达分析以及Genecards数据库构建相关的靶点库。蛋白质-蛋白质相互作用网络确定了核心基因，并通过分子对接进行验证。转录组分析和单细胞表达数据探索了细胞类型特异性表达模式。结果显示甲基-4-羟基苯甲酸与阿尔茨海默病之间存在显著的正因果关联。我们鉴定出198个甲基-4-羟基苯甲酸靶点，其中99个基因与甲基-4-羟基苯甲酸和阿尔茨海默病均相关。确定了六个核心基因（表皮生长因子受体、雌激素受体1、丝裂原活化蛋白激酶3、基质金属蛋白酶9、环氧合酶2、肿瘤蛋白p53）。功能富集涉及神经元信号传导、炎症和代谢。多组学和单细胞分析揭示了关键脑区中核心基因的差异表达。分子对接证实了甲基-4-羟基苯甲酸与这些蛋白质之间的稳定相互作用。本研究证实了甲基-4-羟基苯甲酸与阿尔茨海默病之间的因果关系，揭示了潜在的分子机制和核心基因功能，为发病机制和治疗靶点提供了见解。
