Molecular Mechanisms of Yifei Capsule in Stable COPD Treatment: An Integrated In Silico and Single-cell Transcriptomic Study.
TL;DR
The findings suggest that YFC may exert therapeutic effects in stable COPD through multi-component, multi-target regulation of the PI3K-Akt pathway and related inflammatory signaling networks.
Abstract
INTRODUCTION Yifei Capsule (YFC), a Traditional Chinese Medicine (TCM) formulation, has shown clinical benefit in patients with stable Chronic Obstructive Pulmonary Disease (COPD). However, its molecular mechanisms remain insufficiently understood. This study aimed to systematically investigate the active compounds, key targets, and signaling pathways underlying the therapeutic effects of YFC in stable COPD by integrating computational pharmacology with single-cell transcriptomic validation.
Methods
An integrated workflow combining network pharmacology, molecular docking, and 100 ns Molecular Dynamics (MD) simulations was used to identify bioactive compounds, candidate therapeutic targets, and major signaling pathways of YFC. To externally validate the in silico findings, an independent public single-cell RNA sequencing (scRNA-seq) dataset (GSE249584) containing 54,821 cells from 15 human samples (7 controls and 8 COPD patients) was analyzed to characterize the cell-type-specific expression patterns of hub genes in COPD.
Results
A total of 167 bioactive compounds in YFC and 977 putative targets were identified, of which 222 overlapped with COPD-related targets. Network topology analysis identified SRC, PIK3R1, and STAT3 as major hub genes, and KEGG enrichment analysis indicated that these targets were primarily enriched in the PI3K-Akt signaling pathway (hsa04151, p = 1.23E-15). Molecular docking revealed strong binding affinities between representative compounds and core targets, while MD simulations confirmed the dynamic stability of key complexes, particularly SRC-Korseveriline. scRNA-seq analysis further demonstrated cell-type-specific dysregulation of hub genes in COPD: STAT3 was significantly upregulated in monocyte/macrophage populations (adjusted p = 6.59E-08, log2FC = 0.32), PIK3R1 was downregulated in T cells (adjusted p = 2.05E-20, log2FC = -0.41), and SRC showed bimodal expression, with upregulation in endothelial cells (adjusted p = 0.002, log2FC = 0.38) but downregulation in T cells (adjusted p = 0.03, log2FC = -0.27).
Discussion
These findings suggest that YFC may exert therapeutic effects in stable COPD through multi-component, multi-target regulation of the PI3K-Akt pathway and related inflammatory signaling networks. The cell-type-specific dysregulation of SRC, PIK3R1, and STAT3 supports a nuanced immunomodulatory and vascular-regulatory mechanism, highlighting the value of integrating computational prediction with single-cell transcriptomic evidence.
Conclusion
This multi-scale study provides a mechanistic framework for understanding the action of YFC in stable COPD and identifies SRC, PIK3R1, and STAT3 as plausible core targets. The results support the utility of combining network pharmacology, molecular simulation, and single-cell transcriptomics to dissect the mechanisms of complex herbal medicines. Nevertheless, the present findings remain correlative and require further experimental validation to establish causality.