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本研究基于机器学习与单细胞分析,探索美沙拉嗪所致药物性肝损伤(drug induced liver injury, DILI)铁死亡相关的特征基因,并预测潜在的治疗中药。整合基因表达综合数据库(gene expression omnibus, GEO)中DILI相关数据集,以GSE54254、 GSE102006和GSE169072作为训练集, GSE54257和GSE147866作为验证集。通过差异表达基因(differentially expressed genes, DEGs)分析、加权基因共表达网络分析(weighted gene co-expression network analysis, WGCNA)及铁死亡基因集筛选候选靶点,采用113种组合情形的机器学习模型结合沙普利加性解释(Shapley Additive ex Planations, SHAP)分析筛选关键基因,构建人工神经网络(artificial neural network, ANN)模型与列线图模型评估诊断效能,并对核心基因进行表达差异验证及共表达网络分析。利用基因集富集分析(gene set enrichment analysis, GSEA)、单细胞转录组及细胞通讯分析阐明机制,通过网络药理学与分子对接预测潜在治疗中药。结果显示,共获得111个DILI相关铁死亡靶基因,通过筛选并验证,确定FABP1、 TNFRSF10B、 CSRP2和TYMS可作为美沙拉嗪致DILI的生物标志物。GSEA提示核心基因富集于氧化磷酸化、补体与凝血级联反应、细胞因子-细胞因子受体相互作用等免疫代谢通路。单细胞分析显示核心基因主要表达于单核细胞、巨噬细胞及平滑肌细胞,且巨噬细胞在细胞间通讯网络中交互活性最强。筛选出陈皮、枳实等33味中药,其药性以平、温、微寒为主,药味多为苦、辛、甘,主归肺、肝、胃、脾经,核心功效为理气与清热解毒。分子对接显示活性成分与核心靶点结合稳定。结果表明, FABP1、 TNFRSF10B、 CSRP2和TYMS作为美沙拉嗪相关DILI的潜在诊断生物标志物,具有良好的区分效能,可能通过调控铁死亡通路及巨噬细胞功能参与DILI的发生,筛选出的中药为临床防治提供了新的候选策略。
Abstract：This study integrated machine learning and single-cell analysis to identify ferroptosis-related signature genes in mesalazineinduced drug-induced liver injury( DILI) and to predict potential therapeutic Chinese herbal medicines. DILI-related datasets from the gene expression omnibus( GEO) database were collected. GSE54254, GSE102006 and GSE169072 were used as the training set, while GSE54257 and GSE147866 served as the validation set. Candidate targets were screened through differentially expressed genes( DEGs) analysis, weighted gene co-expression network analysis( WGCNA), and ferroptosis-related gene sets. A total of 113 combination scenarios of machine learning models, combined with Shapley Additive ex Planations( SHAP) analysis, were employed to identify key genes. An artificial neural network( ANN) model and a nomogram model were constructed to evaluate diagnostic performance. Differential expression validation and co-expression network analysis were performed on the core genes. The underlying mechanisms were elucidated using gene set enrichment analysis( GSEA), single-cell transcriptomics, and cell communication analysis, while network pharmacology and molecular docking were applied to predict potential therapeutic Chinese herbal medicines. The results showed that 111 DILI-related ferroptosis target genes were obtained, and four genes—FABP1, TNFRSF10B, CSRP2 and TYMS—were screened and validated as diagnostic biomarkers for mesalazine-induced DILI. GSEA revealed that the core genes were enriched in immunometabolic pathways such as oxidative phosphorylation, the complement and coagulation cascades, and the cytokine-cytokine receptor interaction. Single-cell analysis indicated that the core genes were mainly expressed in monocytes, macrophages, and smooth muscle cells, with macrophages exhibiting the strongest interaction activity in the cell-cell communication network. Thirty-three Chinese herbal medicines, including citri reticulatae pericarpium and aurantii fructus immaturus, were screened. These herbs are predominantly neutral, warm, or slightly cold in nature, with bitter, pungent, and sweet flavors, and mainly belong to the lung, liver, stomach, and spleen meridians, with the core therapeutic effects of regulating qi and clearing heat with detoxification. Molecular docking showed stable binding between the active ingredients and the core targets. The findings indicate that FABP1, TNFRSF10B, CSRP2 and TYMS have good discriminative efficacy as potential diagnostic biomarkers for mesalazine-associated DILI and may participate in the pathogenesis of DILI by regulating ferroptosis pathways and macrophage function. The screened Chinese herbal medicines provide novel candidate strategies for clinical prevention and treatment.
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基本信息:
DOI：10.13417/j.gab.045.000902
中图分类号:R575
引用信息:
[1]强永虎,查瑞瑶,许圣楠,等.美沙拉嗪致肝损伤铁死亡标志物识别及潜在的治疗中药预测[J].基因组学与应用生物学,2026,45(04):902-921.DOI:10.13417/j.gab.045.000902.
基金信息:
安徽省中医药领军人才培养对象项目([2018]23号); 安徽省卫生健康委科研项目(AHWJ2021a021)共同资助
2026-07-14
2026-07-14
2026-07-14