Wu Yeke, Li Jiawei, Liu Min, Gao Ranran, Li Shuang, Hu Qiongying, Xie Yunfei, Li Li
Department of Stomatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jul 2. doi: 10.1007/s00210-025-04320-7.
Periodontitis (PD) and ulcerative colitis (UC) are chronic inflammatory diseases that may share underlying molecular mechanisms, potentially mediated by PANoptosis, which integrates pyroptosis, apoptosis, and necroptosis. Understanding their interaction could unveil novel therapeutic targets. This study aimed to identify key targets and pathways linked to PD and UC, explore the interaction between PANoptosis-related genes and PD-UC-related genes, and predict potential therapeutic targets and drugs for PD-UC. In this study, we acquired datasets from the GEO database, including GSE16134 for PD and GSE87466 for UC. Disease-related targets were identified through differential expression analysis and weighted gene co-expression network analysis. These targets were compared with PANoptosis-related targets and used to form protein-protein interaction networks. Enrichment analyses, such as GO and KEGG, were conducted to investigate the biological significance. Core genes were pinpointed utilizing LASSO and SVM-RFE algorithms, and their expressions were verified in an experimental PD and DSS-induced UC mouse model and single-cell RNA sequencing. A ceRNA network was established, and potential drugs targeting core genes were predicted. Molecular docking simulations were performed to determine binding interactions. As a result, a total of 107 intersected genes were identified, with BAG3, LYN, and APOE recognized as core targets. These genes were significantly associated with immunological processes and inflammatory pathways, as evidenced by enrichment analyses. Histological and molecular validation in mice confirmed their differential expression in PD and UC. Single-cell RNA sequencing revealed cell-type-specific expression of core genes, with Lyn enriched in myeloid cells and Apoe in fibroblasts. A ceRNA network highlighted regulatory interactions, while drug prediction pinpointed potential therapeutic agents for LYN and APOE. In conclusion, the study identifies core genes and their molecular networks bridging PANoptosis with PD and UC, underscoring the potential of BAG3, LYN, and APOE as therapeutic targets. These discoveries establish PANoptosis as a novel therapeutic axis for chronic inflammatory comorbidities, bridging the gap between oral and intestinal mucosal immunity.
牙周炎（PD）和溃疡性结肠炎（UC）是慢性炎症性疾病，可能共享潜在的分子机制，这可能由PAN凋亡介导，PAN凋亡整合了细胞焦亡、凋亡和坏死性凋亡。了解它们之间的相互作用可能会揭示新的治疗靶点。本研究旨在确定与PD和UC相关的关键靶点和通路，探索PAN凋亡相关基因与PD-UC相关基因之间的相互作用，并预测PD-UC的潜在治疗靶点和药物。在本研究中，我们从GEO数据库获取数据集，包括用于PD的GSE16134和用于UC的GSE87466。通过差异表达分析和加权基因共表达网络分析确定疾病相关靶点。将这些靶点与PAN凋亡相关靶点进行比较，并用于构建蛋白质-蛋白质相互作用网络。进行了如GO和KEGG等富集分析以研究其生物学意义。利用LASSO和SVM-RFE算法确定核心基因，并在实验性PD和DSS诱导的UC小鼠模型以及单细胞RNA测序中验证其表达。建立了ceRNA网络，并预测了靶向核心基因的潜在药物。进行分子对接模拟以确定结合相互作用。结果，共鉴定出107个交集基因，其中BAG3、LYN和APOE被确定为核心靶点。富集分析表明，这些基因与免疫过程和炎症通路显著相关。小鼠的组织学和分子验证证实了它们在PD和UC中的差异表达。单细胞RNA测序揭示了核心基因的细胞类型特异性表达，Lyn在髓样细胞中富集，Apoe在成纤维细胞中富集。ceRNA网络突出了调控相互作用，而药物预测确定了LYN和APOE的潜在治疗药物。总之，该研究确定了连接PAN凋亡与PD和UC的核心基因及其分子网络，强调了BAG3、LYN和APOE作为治疗靶点的潜力。这些发现确立了PAN凋亡作为慢性炎症合并症的新治疗轴，弥合了口腔和肠道黏膜免疫之间的差距。
