Quercetin improves airway remodeling in COPD rats by suppressing phenotypic switch of ASMCs via inhibiting the Wnt5a/β-catenin pathway

Background and purpose: Airway remodeling in chronic obstructive pulmonary disease (COPD) is a contributor to airflow limitation, promotes disease progression, and affects disease outcome and prognosis. Quercetin has been identified as a potential therapeutic agent for COPD. Currently, there is insufficient research providing direct evidence to support this hypothesis. The present study investigates the therapeutic effects and the underlying mechanisms of quercetin in the alleviation of airway remodeling in rat models of COPD.

Experimental steps: This study used a network pharmacology approach to predict, for the first time, the potential molecular targets of quercetin in COPD. The effects of quercetin on phenotypic switching and mitochondrial function of ASMCs were assessed in vitro using CCK-8, EdU staining, migration assays, western blotting, and JC-1 staining. Additionally, the interaction between Wnt5a and quercetin was analyzed via molecular docking, and findings were experimentally confirmed using the cellular thermal shift assay (CETSA). Quercetin's influence on airway remodeling in COPD was examined in vivo through pulmonary function evaluation, H&E staining, and Modified Sirius Red staining. Molecular alterations associated with phenotypic switching, oxidative stress, Autophagy and Wnt5a/β-catenin pathway were examined by Western blotting, immunofluorescence, immunohistochemistry, DHE staining and ELISA.

Key results: The results showed that quercetin has a beneficial therapeutic effect on COPD. Its ability to mitigate airway remodeling is linked to modulating Autophagy levels, reducing oxidative stress, alleviating mitochondrial damage, and influencing the phenotypic switch in ASMCs. By increasing oxidative stress tolerance, quercetin reduces mitochondrial damage and regulates the phenotypic switch in ASMCs. Furthermore, quercetin suppresses Autophagy hyperactivation, which subsequently lowers oxidative stress levels in ASMCs. Notably, quercetin modulates Autophagy through the regulation of the Wnt5a/β-catenin signaling pathway.

Conclusion and implications: In conclusion, quercetin demonstrates potential therapeutic effects in COPD by suppressing the Wnt5a/β-cateninsignaling pathway, Autophagy as well as oxidative stress, and thereby alleviating mitochondrial damage and the phenotypic switch in ASMCs. These findings may have clinical applications and offer new insights for the development of COPD treatments.

Autophagy; Chronic obstructive pulmonary disease (COPD); Oxidative stress; Phenotypic switch; Quercetin.