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

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 μM) 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.