Catalpol Protects Against Pulmonary Fibrosis Through Inhibiting TGF-β1/Smad3 and Wnt/β-Catenin Signaling Pathways

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling; however, the molecular mechanisms underlying its occurrence and development are not yet fully understood. Despite it having a variety of beneficial pharmacological activities, the effects of catalpol (CAT), which is extracted from Rehmannia glutinosa, in IPF are not known. In this study, the differentially expressed genes, proteins, and pathways of IPF in the Gene Expression Omnibus database were analyzed, and CAT was molecularly docked with the corresponding key proteins to screen its pharmacological targets, which were then verified using an animal model. The results show that collagen metabolism imbalance, inflammatory response, and epithelial-mesenchymal transition (EMT) are the core processes in IPF, and the TGF-β1/Smad3 and Wnt/β-catenin pathways are the key signaling pathways for the development of pulmonary fibrosis. Our results also suggest that CAT binds to TGF-βR1, Smad3, Wnt3a, and GSK-3β through hydrogen bonds, van der Waals bonds, and other interactions to downregulate the expression and phosphorylation of Smad3, Wnt3a, GSK-3β, and β-catenin, inhibit the expression of cytokines, and reduce the degree of oxidative stress in lung tissue. Furthermore, CAT can inhibit the EMT process and collagen remodeling by downregulating fibrotic biomarkers and promoting the expression of epithelial cadherin. This study elucidates several key processes and signaling pathways involved in the development of IPF, and suggests the potential value of CAT in the treatment of IPF.

Multi‐omics integration reveals a nonlinear signature that precedes progression of lung fibrosis

“…This goes in line with the increased expression of genes related to EMT ( SFRP4 25 and CPXM2 26 ), a process that contributes to fibrosis, in IPF explants compared with NDC. We also observed an upregulation of collagen and other matrix‐associated genes ( CTHRC1 27 and FNDC1 28 among others) previously identified as potential biomarkers of IPF. 27 , 29 , 30 , 31 Notably, FNDC1 was the most important feature predicting established disease in our ML model for Factor1.…”

Molecular mechanisms of alveolar epithelial cell senescence and idiopathic pulmonary fibrosis: a narrative review

“…WNT components, including WNT3a, β-catenin, and pGSK-3β proteins, are increased during IPF development, and decreased GSK-3β expression has also been observed in mouse fibrotic lungs ( 61 , 62 ). Therefore, inhibition of the WNT/β-catenin signaling pathway leads to attenuation of IPF ( 63 ). Lehman et al reported that WNT/β-catenin activity was increased in ATII cells of aged mice (16–24 months) compared to that in young mice (3 months), whereas chronic typical WNT/β-catenin activation for seven days induced cellular senescence ( 64 ).…”

Dec1 Deficiency Ameliorates Pulmonary Fibrosis Through the PI3K/AKT/GSK-3β/β-Catenin Integrated Signaling Pathway

“…As reported previously, the origin of fibro-blasts and myofibroblasts in PF is still controversial; however, EMT in AEC2s is believed to be a significant source of the lung fibroblasts and myofibroblasts in PF ( Willis et al, 2006 ; Chapman, 2011 ). Several reports have suggested that EMT is an important mechanism in the development of PF ( Zhang et al, 2019 ; Chen et al, 2020 ; Yang et al, 2020 ). TGF-β1, one of the major profibrotic cytokines in IPF, is widely used to induce EMT in epithelial cells to explore the mechanism of PF ( Qian et al, 2019 ; Kim et al, 2020 ).…”