Dihydromyricetin restores mucus hypersecretion in Air-Liquid interface cultures in COPD by targeting the SRC-MAPK...

Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition characterized by chronic respiratory symptoms due to bronchitis and emphysema, often leading to persistent airflow obstruction. Dihydromyricetin (DHM), a Garcinia cambogia extract, exhibited anti-inflammatory, antitumor, and antioxidant effects without significant toxicity to normal cells in vitro and in vivo. This study aimed to investigate the effect of DHM on mucus hypersecretion in air-liquid interface (ALI) cultures in COPD and to explore the underlying mechanism. Bronchial epithelial cells from five COPD patients and five Non-COPD subjects were collected by bronchoscopy at ALI. ALI cultures from COPD and Non-COPD subjects, as well as airway organoids, were differentiated for 2 weeks subsequently treated with DHM (50 microM) for an additional 2 weeks. The potential molecular mechanisms of DHM were investigated using network pharmacology analysis and molecular docking techniques. DHM reduced mucus hypersecretion and increased cilia number in ALI cultures (Average fold change = 6.52, P = 0.0033; average fold change = 11.56, P = 0.0011) and airway organoids (average fold change = 1.68, P = 0.0096; average fold change = 1.60, P = 0.0130) from COPD patients. Network pharmacology analysis, supported by experimental validation, confirmed that DHM alleviated COPD-related mucus hypersecretion and improved ciliary morphology by binding to SRC and regulating autophagy-related proteins and the MAPK signaling pathway. These findings suggest that DHM could be a potential therapeutic agent for preventing mucus hypersecretion in COPD. This study is the first to combine network pharmacology analysis to investigate the mechanism of DHM in alleviating COPD-associated mucus hypersecretion.