Cremades-Jimeno Lucía, López-Ramos María, Fernández-Santamaría Rubén, De Pedro María Ángeles, Mahillo Ignacio, Rosales-Ariza Cristina, Olaguibel José María, Pozo Victoria Del, Caballero María Luisa, Luna-Porta Juan Alberto, Quirce Santiago, Barroso Blanca, Betancor Diana, Valverde-Monge Marcela, Sastre Joaquín, Baos Selene, Cárdaba Blanca
Immunology Department, IIS-Fundación Jiménez Díaz-UAM, 28040 Madrid, Spain.
Biostatistics and Epidemiology Unit, University Hospital Fundación Jiménez Díaz, 28040 Madrid, Spain.
Int J Mol Sci. 2025 Jun 28;26(13):6240. doi: 10.3390/ijms26136240.
Asthma is a chronic and heterogeneous inflammatory airway disease with diverse clinical endotypes and limited curative treatment options. Recent systems biology analyses identified four potential molecular -AKT1, MAPK13, STAT1, and TLR4-as candidate regulators of asthma-associated signaling pathways. This study aimed to validate the expression of these four proteins and their downstream signaling elements in peripheral blood mononuclear cells (PBMCs) from patients with allergic asthma (AA), nonallergic asthma (NA), and healthy controls (HC), to explore their potential as biomarkers or therapeutic targets. For that, PBMC samples were collected from 45 AA patients, 17 NA patients, and 15 HC subjects. Gene and protein expression of AKT1, MAPK13, STAT1, and TLR4 were quantified using RT-qPCR and Western blotting. Expression patterns were compared across groups and stratified by asthma severity. Correlations with clinical parameters (FEV1, FVC, FeNO, IgE, eosinophil counts) and treatment regimens were also assessed. All four target genes showed significantly reduced expression in asthma patients compared to controls ( < 0.001), with the most marked downregulation in NA patients. At the protein level, MAPK13 and TLR4 showed significant differential expression. Stratification by severity revealed a stepwise reduction in gene expression in AA patients, correlating with disease severity, whereas NA patients showed uniformly low expression regardless of severity. Multiple pathway-related genes, including , , , and , were also downregulated, particularly in NA patients. Notably, differential correlations were observed between gene expression and lung function parameters in AA vs. NA groups. In conclusion, this study supports the potential involvement of AKT1, MAPK13, STAT1, and TLR4 in asthma pathogenesis and highlights differences between allergic and nonallergic asthma at the molecular level. These proteins and their associated pathways may serve as future targets for biomarker development or endotype-specific therapies. Further studies in larger and more diverse cohorts, including functional validation, are warranted.
哮喘是一种慢性异质性炎症性气道疾病，具有多种临床亚型且治疗选择有限。最近的系统生物学分析确定了四种潜在的分子——AKT1、MAPK13、STAT1和TLR4——作为哮喘相关信号通路的候选调节因子。本研究旨在验证这四种蛋白质及其下游信号元件在过敏性哮喘（AA）患者、非过敏性哮喘（NA）患者和健康对照（HC）外周血单个核细胞（PBMC）中的表达，以探索它们作为生物标志物或治疗靶点的潜力。为此，收集了45例AA患者、17例NA患者和15例HC受试者的PBMC样本。使用RT-qPCR和蛋白质印迹法对AKT1、MAPK13、STAT1和TLR4的基因和蛋白质表达进行定量。比较各组之间的表达模式，并按哮喘严重程度进行分层。还评估了与临床参数（FEV1、FVC、FeNO、IgE、嗜酸性粒细胞计数）和治疗方案的相关性。与对照组相比，所有四个靶基因在哮喘患者中的表达均显著降低（<0.001），在NA患者中下调最为明显。在蛋白质水平上，MAPK13和TLR4表现出显著的差异表达。按严重程度分层显示，AA患者的基因表达呈逐步下降，与疾病严重程度相关，而NA患者无论严重程度如何均表现出一致的低表达。包括 、 、 和 在内的多个与通路相关的基因也下调，尤其是在NA患者中。值得注意的是，在AA组和NA组中，基因表达与肺功能参数之间观察到不同的相关性。总之，本研究支持AKT1、MAPK13、STAT1和TLR4可能参与哮喘发病机制，并突出了过敏性哮喘和非过敏性哮喘在分子水平上的差异。这些蛋白质及其相关通路可能成为未来生物标志物开发或亚型特异性治疗的靶点。有必要在更大、更多样化的队列中进行进一步研究，包括功能验证。
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