Targeting CDK2 ameliorates allergic asthma through suppression of epithelial chemokine production and T cell inflammatory responses.

Allergic asthma is a chronic inflammatory airway disease driven by dysregulated type 2 immunity and aberrant epithelial-immune crosstalk. Despite advances in biologic therapies, many patients remain refractory to current treatments, underscoring the need for novel strategies that simultaneously target multiple pathogenic axes. Here, we show that cyclin-dependent kinase 2 (CDK2) is upregulated in bronchoalveolar lavage cells from asthmatic patients and its expression correlates with enhanced cell cycle activity, inflammatory signatures, and T cell activation in bronchial epithelium across six independent cohorts. In an ovalbumin (OVA)-induced murine model, pharmacological inhibition with a highly selective small-molecule CDK2 inhibitor (CDK2i) markedly alleviated airway hyperresponsiveness (AHR), eosinophilic inflammation, mucus hypersecretion, and peribronchial fibrosis, with effects comparable to those of dexamethasone. Mechanistically, CDK2i suppressed chemokine production in airway epithelial cells, thereby reducing T cell recruitment, while concurrently inducing G1/S cell-cycle arrest in T lymphocytes and blunting their production of Th2 cytokines. Integrated transcriptomic and functional analyses suggested that CDK2 may be involved in two pathways: epithelial-driven immune cell trafficking and T cell clonal expansion. Together, these findings suggest that selective CDK2 inhibition represents a promising experimental strategy for attenuating allergic airway inflammation and warrants further investigation in preclinical models of asthma.