Integrated multi-omics and experimental validation reveal naringenin alleviates allergic rhinitis with TP53 as a key mediator in immune microenvironment remodeling

Allergic rhinitis (AR) is a prevalent IgE-mediated inflammatory disease with limited treatment options and significant side effects associated with conventional therapies. Naringenin, a natural flavonoid, shows anti-allergic potential; however, its system-level mechanisms and specific cellular targets remain unclear. This study systematically investigates the candidate targets of naringenin and elucidates its potential mechanisms of action in AR using integrative multi-omics and experimental validation.

We combined transcriptomic analysis of public datasets (GSE75011 and GSE44037), network pharmacology, weighted gene co-expression network analysis (WGCNA), and machine learning to identify core targets. Molecular docking assessed the binding affinity between naringenin and key targets. In vivo validation was performed in an ovalbumin-induced AR mouse model, evaluating symptom scores, serum IgE and cytokines, histopathology, and Trp53 protein expression. Single-cell RNA sequencing was performed on nasal mucosa tissues from control and AR mice.

We identified 7 and 38 overlapping target genes through differentially expressed genes–target and WGCNA–target intersections, respectively. Following protein–protein interaction network and machine learning refinement, 9 core genes were identified, with four hub targets—BCL2, PPARG, IL-1β, and TP53—showing strong binding to naringenin. TP53 served as a central transcriptional regulator. In vivo, naringenin significantly reduced allergic symptoms, inflammatory biomarkers, and Trp53 overexpression. Single-cell RNA sequencing of the AR microenvironment revealed TP53 upregulation specifically in B cells, T cells, and plasmacytoid dendritic cells (pDCs), and highlighted the concomitant enrichment of autophagy and lysosomal pathways in pDCs.

Naringenin alleviates AR, and this effect is associated with the downregulation of TP53, suggesting TP53 as a candidate mediator in its mechanism of action and providing a foundation for future mechanistic and therapeutic studies in AR.