Dihydroartemisinin alleviates allergic airway inflammation by suppressing the PI3K-AKT signaling axis: integrated network pharmacology and experimental validation

Background Allergic asthma is a heterogeneous inflammatory airway disorder driven by dysregulated immune responses and epithelial–immune crosstalk. Dihydroartemisinin (DHA), an active derivative of artemisinin, exhibits broad anti-inflammatory and immunomodulatory properties; however, its mechanistic role in allergic asthma remains incompletely defined. Methods Network pharmacology was employed to predict potential therapeutic targets and signaling pathways of DHA in asthma. These predictions were validated in a house dust mite (HDM) induced murine asthma model and HDM stimulated human bronchial epithelial (HBE) cells using histopathology, flow cytometry, RT-qPCR, Western blotting, ELISA, and molecular docking. Results Network analysis identified nine hub targets and highlighted the PI3K-AKT pathway as a central regulatory axis. In vivo, DHA markedly attenuated airway inflammation, reduced eosinophil and neutrophil infiltration, and decreased Th2 cytokine production. In HDM-stimulated HBE cells, DHA suppressed pro-inflammatory cytokine expression and downregulated EGFR, MMP9, and PTGS2. Mechanistically, DHA inhibited activation of the PI3K-AKT-mTOR signaling cascade both in vitro and in vivo, consistent with molecular docking predictions demonstrating stable binding of DHA to PI3K related targets. Conclusions DHA alleviates allergic airway inflammation predominantly through suppression of the PI3K-AKT signaling axis, thereby modulating epithelial inflammatory responses and type 2 immunity. These findings provide mechanistic insight into DHA-mediated immunoregulation and support its potential repositioning as a therapeutic candidate for allergic asthma.