目的 筛选与溃疡性结肠炎（ulcerative colitis，UC）和雷公藤多苷（Tripterygium wilfordii polycoride，TWP）治疗应答均相关的核心基因，探讨TWP在缓解UC炎症中的潜在机制。方法 构建2,4,6-三硝基苯磺酸（2,4,6-trinitrobenzenesulfonic acid，TNBS）/乙醇诱导的UC大鼠模型，利用Affymetrix GeneChip^® Rat Genome 230 2.0芯片，开展表达谱芯片分析以明确与UC炎症及TWP治疗应答均相关的核心基因，并利用富集分析和和IPA分析发现与核心基因高度相关的通路，利用慢病毒转染进行验证，通过qRT-PCR和免疫荧光检测核心基因的表达。结果 大鼠结肠表达谱芯片检测结果表明，TWP可显著下调模型组中上调的1 056个差异表达基因，其中S100钙结合蛋白A8（S100 calcium binding protein A8，S100A8）的表达变化最为显著，提示其可能是TWP调控UC炎症的核心靶基因。富集分析、IPA网络分析及慢病毒转染结果进一步表明，S100A8主要通过调控核因子-κB（nuclear factor-κB，NF-κB）信号通路及相关炎症因子发挥作用。免疫荧光与qRT-PCR结果也证实，TWP干预可显著降低S100A8在UC模型中的表达，抑制作用呈剂量相关性。结论 S100A8可能是TWP调控UC炎症的关键靶点，其调控机制可能与NF-κB通路相关，为UC的药物干预提供了新的分子靶点和潜在的治疗策略。

ObjectiveTo identify core genes associated with ulcerative colitis (UC) pathogenesis and Tripterygium wilfordii polycoride (TWP) therapeutic response, while elucidating the molecular pathways through which TWP mitigates intestinal inflammation.Methods A 2,4,6-trinitrobenzenesulfonic acid (TNBS)/ethanol-induced UC rat model was established. Genome-wide transcriptomic profiling was performed using the Affymetrix GeneChip^® Rat Genome 230 2.0 microarray to identify inflammation-related differentially expressed genes (DEGs) modulated by TWP. Enrichment analysis and IPA were employed to delineate critical signaling pathways. Key findings were validated via qRT-PCR and immunofluorescence assays.Results Microarray analysis revealed that TWP treatment significantly down-regulated 1 056 inflammation-associated DEGs up-regulated in UC rats, with S100 calcium binding protein A8 (S100A8) exhibiting the most prominent suppression. Functional enrichment and IPA network modeling implicated S100A8 in nuclear factor-κB (NF-κB) signaling pathway modulation and inflammatory cytokine regulation. Lentiviral transduction experiments further confirmed this pathway association. Both immunofluorescence and qRT-PCR analysis demonstrated that TWP dose-dependently inhibited S100A8 expression in colonic tissues of UC rats.Conclusion S100A8 serves as a pivotal therapeutic target through which TWP ameliorates UC-associated inflammation, primarily via NF-κB pathway inhibition. This study unveils novel molecular targets and mechanistic insights for developing UC therapeutics.

R285.5

国家自然科学基金面上项目（81273903）；国家自然科学基金面上项目（81673798）；国家自然科学基金面上项目（81973617）