Chaihu‐Guizhi Decoction Attenuates Airway Remodelling in COPD Mice via the TGF‐β1/Smads Signalling Pathway: An Integrated Proteomic and Metabolomic Analysis

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is characterised by persistent airway injury and remodelling, and the mechanisms by which Chai‐Hu‐Gui‐Zhi Decoction (CGD) acts in COPD remain unclear. This study investigated whether CGD attenuates airway remodelling through the TGF‐β1/Smads–EMT–ECM signalling axis. A mouse COPD model was established by cigarette‐smoke exposure plus intranasal lipopolysaccharide. After model induction, mice received dexamethasone acetate or low‐, medium‐ or high‐dose CGD for 28 days. UHPLC‐MS/MS, network pharmacology, molecular docking, molecular dynamics, proteomics, metabolomics, ELISA, western blotting, RT‐PCR, pulmonary function testing and histopathology were integrated. CGD dose‐dependently improved pulmonary function and lung pathology and reduced BALF total protein, NO, VEGF, IFN‐γ, MPO, CXCL1 and serum 8‐OHdG. Multi‐omics and network analyses implicated phenylalanine/tyrosine/tryptophan biosynthesis, the histidine–glutamate–hypoxanthine axis, MAPK, PI3K–Akt and TGF‐β1‐related pathways. Validation showed that CGD decreased TGF‐β1, p‐SMAD2/3, SMAD2/3, MMP‐9 and TIMP‐1; increased SMAD7 and E‐cadherin; and regulated Smad2/Smad3/Smad7 mRNA. CGD may attenuate COPD airway remodelling, in association with suppressed TGF‐β1/Smads signalling, restored SMAD7‐mediated feedback, limited EMT and rebalanced ECM remodelling.