Network-guided discovery of Zeqi Decoction as a PPARγ-targeted therapy for pulmonary fibrosis

Pulmonary fibrosis (PF) is a chronic and fatal lung disease with limited effective therapeutic options. Zeqi Decoction (ZQD), a classical TCM formula for respiratory disorders, shows multicompound therapeutic potential for PF.

This study aimed to evaluate its antifibrotic activity, identified active constituents, and elucidated therapeutic targets and mechanisms.

ZQD was prioritized and tested in bleomycin-induced pulmonary fibrosis mice and in bleomycin- or TGF-β1-stimulated alveolar epithelial cells. Core compounds of ZQD and those entering the plasma and lung tissues were identified by HPLC-MS, and potential targets were predicted via network pharmacology and transcriptomics. Molecular dynamics and surface plasmon resonance (SPR) validated binding to peroxisome proliferator-activated receptor γ (PPARγ). Lipidomic profiling assessed downstream metabolic changes.

ZQD significantly alleviated PF and showed a positive trend in reducing mortality, decreasing collagen deposition, and improving lung function in vivo. Network pharmacology integrated with transcriptomics and molecular docking revealed key target as PPARγ along with baicalein, naringenin, and luteolin as core compounds, which were further validated by molecular dynamics simulation and SPR to exhibit high-affinity binding. In vitro, ZQD and its core compounds protected alveolar epithelial cells from bleomycin-induced injury and inhibited TGF-β1-induced epithelial-mesenchymal transition (EMT). Lipidomic profiling showed restoration of disordered lipid metabolites, supporting activation of PPARγ- associated metabolic pathways.

Network-guided screening and experimental validation identify ZQD and its core compounds as a promising antifibrotic therapy targeting PPARγ, offering a novel mechanism-based strategy that may address unmet needs compared to current drugs, which primarily slow lung function decline without extending survival.