Bai Qiaoyun, Wang Chongyang, Ding Ningpo, Wang Zhiguang, Liu Ruobai, Li Liangchang, Piao Hongmei, Song Yilan, Yan Guanghai
Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji 133002, PR China.
Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Respiratory Medicine, Affiliated Hospital of Yanbian University, Yanji 133000, PR China.
Phytomedicine. 2025 Jun;141:156657. doi: 10.1016/j.phymed.2025.156657. Epub 2025 Mar 17.
We investigated the mechanism by which eupalinolide B (EB) regulates DEK protein ubiquitination and degradation, and its impact on DEK-mediated receptor-interacting protein kinase 1 (RIPK)-PANoptosis pathway in allergic asthma.
In vitro studies were conducted on human bronchial epithelial cells (BEAS-2B) treated with EB and human-recombinant DEK. Mass spectrometry analysis, RNA sequencing, molecular docking, and functional assays were used to assess the interactions and effects of EB, DEK, and ring finger protein 149 and 170 (RNF149 and RNF170). In vivo experiments involved a house dust mite-induced asthma model in mice and evaluation of airway inflammation, DEK expression, and PANoptosis markers.
In vitro, EB could bind to DEK. RNF149 and RNF170 were identified as regulatory factors of DEK, polyubiquitinating the K349 site in the DEK coding DNA sequence region 270-350 through K48 linkages and leading to its degradation. RNA sequencing showed that DEK overexpression upregulated the expression of genes such as RIPK1, FADD, and Caspase 8. Treatment with DEK siRNA or EB reduced the activation of the RIPK1-PANoptosis pathway in BEAS-2B-DEK cells. In vivo, EB significantly reduced the levels of DEK in house dust mite-induced mice and alleviated pulmonary inflammatory cell infiltration, goblet cell hyperplasia, collagen fiber deposition, and eosinophil proportion in BALF. Knocking out the DEK gene reduced RIPK1-induced PANoptosis, and inhibited airway inflammation and cell apoptosis.
EB promotes the degradation of DEK by RNF149 and RNF170, inhibits the RIPK1-PANoptosis pathway, and may effectively suppress asthma. EB may become a potential drug for treating airway inflammation in asthma.
我们研究了榄香醇内酯B（EB）调节DEK蛋白泛素化和降解的机制，及其对变应性哮喘中DEK介导的受体相互作用蛋白激酶1（RIPK）-PAN凋亡途径的影响。
对用EB处理的人支气管上皮细胞（BEAS-2B）和人重组DEK进行体外研究。采用质谱分析、RNA测序、分子对接和功能测定来评估EB、DEK以及环指蛋白149和170（RNF149和RNF170）之间的相互作用和影响。体内实验采用屋尘螨诱导的小鼠哮喘模型，并评估气道炎症、DEK表达和PAN凋亡标志物。
在体外，EB可与DEK结合。RNF149和RNF170被鉴定为DEK的调节因子，通过K48连接在DEK编码DNA序列区域270-350中的K349位点进行多聚泛素化并导致其降解。RNA测序显示DEK过表达上调了RIPK1、FADD和半胱天冬酶8等基因的表达。用DEK siRNA或EB处理可降低BEAS-2B-DEK细胞中RIPK1-PAN凋亡途径的激活。在体内，EB显著降低了屋尘螨诱导小鼠的DEK水平，并减轻了肺部炎症细胞浸润、杯状细胞增生、胶原纤维沉积以及BALF中嗜酸性粒细胞比例。敲除DEK基因可减少RIPK1诱导的PAN凋亡，并抑制气道炎症和细胞凋亡。
EB促进RNF149和RNF170介导的DEK降解，抑制RIPK1-PAN凋亡途径，并可能有效抑制哮喘。EB可能成为治疗哮喘气道炎症的潜在药物。
