Integrated immune and programmed cell death analysis identifies NR4A2 as a candidate blood biomarker in asthma

Background Asthma is a heterogeneous chronic airway disease in which both immune dysregulation and programmed cell death (PCD) contribute to disease pathogenesis. However, the molecular crosstalk linking these processes remains incompletely understood. This study aimed to identify key genes associated with immune-PCD interactions in asthma and to evaluate their potential clinical relevance. Methods Public transcriptomic datasets were analyzed using single-sample gene set enrichment analysis (ssGSEA) to quantify immune-cell infiltration and PCD-related signatures in asthma and control samples. Candidate genes were identified by intersecting module genes, differentially expressed genes (DEGs), immune-related genes, and PCD-related genes. Key genes were further screened using least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), and Boruta algorithms. GSEA and single-cell RNA sequencing analyses were performed to explore potential biological pathways, cell-type distribution, and intercellular communication. Peripheral blood samples from 57 asthmatic patients and 30 non-asthmatic controls were collected for qPCR validation, and associations with fractional exhaled nitric oxide (FeNO) and eosinophil counts were assessed. Results 11 immune cell types and 7 PCD categories differed significantly between asthma and control groups. Nine candidate immune-PCD genes were identified, from which three key genes (NRAS, JUN, and NR4A2) were subsequently identified by overlapping the outputs of LASSO, SVM-RFE, and Boruta, and showed high diagnostic performance for asthma (AUC: 1.00, 0.97, and 0.99, respectively). GSEA suggested that these key genes may be involved in asthma-related biological processes through natural killer (NK) cell-mediated cytotoxicity and Toll-like receptor signaling pathways. Single-cell analysis indicated that the key genes were predominantly expressed in T cells and NK cells, with potential intercellular communication via multiple HLA–CD8 ligand–receptor pairs. In peripheral blood validation, NR4A2 expression was significantly reduced in asthma and was negatively correlated with FeNO and eosinophil levels, whereas no significant expression differences were observed for NRAS or JUN. Conclusion NR4A2 was identified as a key immune-PCD-associated gene in asthma and may serve as a candidate diagnostic biomarker. These findings provide a framework for investigating immune-PCD crosstalk in asthma and support further mechanistic and translational studies of NR4A2.