炎症性肠病中的广泛铜死亡景观。

BACKGROUND: Cuproptosis, a genetic process of copper-dependent cell death linked to mitochondria respiration, demonstrates its correlation with inhibiting tumoral angiogenesis and motility. Recent studies have developed systematic bioinformatics frameworks to identify the association of cuproptosis with tumors but any non-neoplastic diseases. Therefore, against the background of an increased incidence of inflammatory bowel disease (IBD), the landscape of cuproptosis regulation in IBD is a critical need to be investigated. METHODS: The differentially expressed cuproptosis-related genes (DECRGs) were identified with human sequencing profiles for four inflammatory digestive disorders. Another four independent IBD datasets from GEO were used as a validation cohort. And experimental mice model provides another validation method. Using single sample gene set enrichment analysis (ssGSEA), receiver operating characteristic (ROC) curve, CIBERSORT, and consensus clustering algorithms, we explored the association between immune score and cuproptosis-related genes, as well as the diagnostic value of these genes. Molecular docking screened potential interaction of IBD drugs with the structural regulator by Autodock Vina. RESULTS: Cuproptosis-related regulators exhibited extensive differential expression in Crohn's Disease (CD), Ulcerative Colitis (UC), Celiac Disease (CEL), and IBD-induced cancer (IBD-CA) that share common differential genes (PDHA1, DBT, DLAT, LIAS). The differential expression of DECRGs was reverified in the validated cohort and immunohistochemistry assay. Moreover, the cell signaling pathways and ontology mainly focused on the mitochondrial respiratory function, which was highly enriched in Gene set enrichment analysis (GSEA). According to ssGSEA and ROC, when considering the four regulators, which showed robust association with immune infiltration in IBD, the area under the ROC (AUC) was 0.743. In addition, two clusters of consensus clustering based on the four regulators exhibit different immune phenotypes. According to molecular docking results, methotrexate gained the highest binding affinity to the main chain of key cuproptosis-related regulators compared with the remaining ten drugs. CONCLUSION: Cuproptosis-related regulators were widely linked to risk variants, immune cells, immune function, and drug efficacy in IBD. Regulation of cuproptosis may deeply influence the occurrence and development of patients with IBD.

背景：铜死亡是一种与线粒体呼吸相关的铜依赖性细胞死亡的遗传过程，它显示出与抑制肿瘤血管生成和运动性的相关性。最近的研究已经开发出系统的生物信息学框架来识别铜死亡与肿瘤的关联，但与任何非肿瘤性疾病无关。因此，在炎症性肠病（IBD）发病率增加的背景下，研究 IBD 中铜死亡调节的情况是非常必要的。

方法：通过人类四种炎症性消化疾病的测序图谱，确定差异表达的铜死亡相关基因（DECRGs）。另外四个来自 GEO 的独立 IBD 数据集被用作验证队列。实验小鼠模型提供了另一种验证方法。使用单样本基因集富集分析（ssGSEA）、受试者工作特征（ROC）曲线、CIBERSORT 和共识聚类算法，我们探讨了免疫评分与铜死亡相关基因之间的关联，以及这些基因的诊断价值。分子对接通过 Autodock Vina 筛选 IBD 药物与结构调节剂之间的潜在相互作用。

结果：铜死亡相关调节剂在克罗恩病（CD）、溃疡性结肠炎（UC）、乳糜泻（CEL）和 IBD 诱导的癌症（IBD-CA）中表现出广泛的差异表达，这些疾病有共同的差异基因（PDHA1、DBT、DLAT、LIAS）。在验证队列和免疫组织化学检测中，对 DECRG 的差异表达进行了重新验证。此外，细胞信号通路和本体论主要集中在线粒体呼吸功能上，这在基因集富集分析（GSEA）中高度富集。根据 ssGSEA 和 ROC，当考虑四个与 IBD 中免疫浸润有强关联的调节剂时，ROC 的曲线下面积（AUC）为 0.743。此外，基于四个调节剂的两种共识聚类聚类表现出不同的免疫表型。根据分子对接结果，与其余十种药物相比，甲氨蝶呤与关键铜死亡相关调节剂的主链具有最高的结合亲和力。

结论：铜死亡相关调节剂与 IBD 中的风险变异、免疫细胞、免疫功能和药物疗效广泛相关。铜死亡的调节可能会深刻影响 IBD 患者的发生和发展。