Xiaoqinglong Decoction Suppresses M1 Macrophage Polarization in COPD via the MET/AKT/HK2 Axis: An Integrated Multi-Omics Analysis.

ETHNOPHARMACOLOGICAL RELEVANCE Xiaoqinglong Decoction (XQLD), a classic herbal formula for respiratory diseases, is clinically effective against chronic obstructive pulmonary disease (COPD). However, whether its anti-inflammatory effects involve modulation of macrophage immunometabolism remains unknown.

Aim

OF THE STUDY This study investigated whether XQLD suppresses M1 macrophage polarization in COPD by modulating glycolysis-related pathways.

Materials And Methods

COPD was induced in rats by alternate intratracheal instillation of papain (Papa) and lipopolysaccharide (LPS). After modeling, the rats received XQLD at high, medium, and low doses, while a separate group received dexamethasone as the positive control. Therapeutic effects on pulmonary function and lung pathology were evaluated, along with M1 polarization by immunofluorescence and other assays. Core pathways were identified through transcriptomic-metabolomic integration. In vitro, XQLD-containing serum was used to treat THP-1-derived M1 macrophages, and M1 polarization, glycolytic indicators, and MET/AKT/HK2 pathway proteins were assessed following treatment with 2-DG, HK2 overexpression, or HGF.

Results

XQLD dose-dependently improved pulmonary function and lung pathology, and reduced M1 infiltration. Multi-omics identified MET and HK as central nodes; XQLD reversed aberrant MET/AKT/HK2 expression in vivo. In vitro, XQLD-containing serum inhibited M1 polarization, glycolytic flux, and HGF-induced MET/AKT/HK2 signaling, with its effects partially reversed by HK2 overexpression.

Conclusion

XQLD attenuates M1 macrophage-driven airway inflammation by normalizing the MET/AKT/HK2 signaling-metabolic axis and suppressing, at least in part, HK2-dependent glycolysis. These findings provide a novel immunometabolic mechanism for the traditional anti-inflammatory efficacy of XQLD in COPD.