【摘要】 目的 探讨程序性死亡受体1(PD-1)抑制剂相关急性肾损伤（AKI）的分子机制。方法 采用网络毒理学方法从多个数据库筛选重叠靶点，随后利用STRING数据库和Cytoscape软件构建蛋白质-蛋白质相互作用（PPI）网络，进行基因本体论（GO）功能和京都基因与基因组百科全书（KEGG）通路富集分析，并对从基因表达综合数据库（GEO）中获取的PD-1抑制剂治疗小鼠的肾组织转录组数据进行分析。结果 共获得176个PD-1抑制剂与AKI的交集靶点及10个核心靶点。交集靶点在磷脂酰肌醇3-激酶/蛋白激酶B(PI3K-Akt)信号通路、辅助性T细胞17(Th17)分化以及白细胞介素-17(IL-17)信号通路中富集。转录组分析进一步证实IL-17信号通路的显著激活。结论 PD-1抑制剂可能促进Th17细胞分化、增强IL-17信号，进而介导肾脏局部免疫炎症损伤；IL-17可作为早期诊断生物标志物，靶向抑制IL-17可能是一种潜在的治疗策略。更多还原

【Abstract】 Objective To explore the molecular mechanism of programmed death-1(PD-1) inhibitor associated acute kidney injury(AKI). Methods A network toxicology approach was employed to screen overlapping targets from multiple databases, with subsequent construction of a proteinprotein interaction(PPI) network using STRING and Cytoscape, performance of Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses, and analysis of transcriptomic data from renal tissues of PD-1 inhibitor treated mice obtained from the Gene Expression Omnibus(GEO) database. Results A total of 176 overlapping targets of PD-1 inhibitor and AKI, along with 10 hub targets, were identified. These targets were enriched in the Phosphatidylinositol-3 kinase/Protein Kinase B(PI3K-Akt) signaling pathway, T helper cell 17(Th17) differentiation, and interleukin 17(IL-17) signaling pathway. Significant activation of the IL-17 signaling pathway was further confirmed by transcriptomic analysis. Conclusion PD-1 inhibitors may promote Th17 cell differentiation and enhance IL-17 signaling, thereby mediating local renal immune inflammatory injury. IL-17 may serve as a biomarker for early diagnosis, and targeted inhibition of IL-17 may be a potential therapeutic strategy.更多还原