Androgen-mediated DKK1 upregulation in bronchial epithelial cells suppresses Th2 response and ameliorates asthma

Asthma is a chronic airway disease where androgens play a regulatory role. Dickkopf-1 (DKK1), a secreted glycoprotein, is positively correlated with androgens. This study aims to explore whether androgens upregulate DKK1 to inhibit Th2 response, potentially alleviating asthma. First, an asthma model was established using immunodeficient male mice. These mice were then divided into five groups and administered dihydrotestosterone (DHT) and/or the DKK-1 inhibitor WAY-262,611. Airway inflammation and lung tissue damage were assessed in each group. Furthermore, bronchoalveolar lavage fluid (BALF) inflammatory markers, the helper T cell 1/helper T cell 2 (Th1/Th2) ratio, and relevant parameters in serum and lung tissue were evaluated. Next, we established an asthma cell model using airway epithelial cells (BECs) and dust mites (HDM) stimulation. After treating with negative control (si-NC) and DKK1-targeted small interfering RNA (si-DKK1), five cell groups were established, with DHT treatment included. We assessed DHT's impact on DKK1 expression in BECs, then co-cultured these five cell groups with CD4⁺ T cells to verify links to Th1/Th2-related factors. Firstly, the in vivo experiments showed that DHT attenuated asthma-induced lung damage and inflammation, reduced Th2's proportion, and normalized Th1/Th2 balance. Co-treatment with WAY-262,611 reversed DHT's protection impact. Subsequently, in vitro cell experiments confirmed that DHT suppressed Th2 response; siRNA-mediated DKK1 knockdown abrogated this suppression. Androgens promote the expression of DKK1 in BECs, thereby inhibiting Th2 response and ultimately improving asthma.

The online version contains supplementary material available at https://doi.org/10.1007/s10616-026-01067-8.