MEOX1 triggers myofibroblast apoptosis resistance, contributing to pulmonary fibrosis in mice
Ling Jin1,2,3, Bo Bao1,2,3, Xiao-Ting Huang4
1Department of Physiology, School of Basic Medical Science, Central South University, Changsha, China.
Abstract:
The apoptosis resistance of myofibroblasts is a hallmark in the irreversible progression of pulmonary fibrosis (PF). While the underlying molecular mechanism remains elusive. In this study, we unveiled a previously unrecognized mechanism underlying myofibroblast apoptosis resistance during PF. Our investigation revealed heightened expression of mesenchyme homeobox 1 (MEOX1) in the lungs of idiopathic pulmonary fibrosis (IPF) patients and bleomycin-induced PF mice. Silencing MEOX1 significantly attenuated PF progression in mice. In vitro, we found a notable increase in MEOX1 expression in transforming growth factor-β1 (TGF-β1)-induced myofibroblasts. Silencing MEOX1 enhanced apoptosis of myofibroblasts. Mechanistically, we identified G-protein signaling pathway regulatory factor 4 (RGS4) as a critical downstream target of MEOX1, as predicted by bioinformatics analysis. MEOX1 enhanced apoptosis resistance by upregulating RGS4 expression in myofibroblasts. In conclusion, our study highlights MEOX1 as a promising therapeutic target for protecting against PF by modulating myofibroblast apoptosis resistance.
Insights
Pulmonary fibrosis involves myofibroblast apoptosis resistance. This study identifies mesenchyme homeobox 1 (MEOX1) as a key factor promoting this resistance by upregulating RGS4, offering a potential therapeutic target for pulmonary fibrosis.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Molecular Mechanisms
Background:
- Myofibroblast apoptosis resistance is central to irreversible pulmonary fibrosis (PF).
- The precise molecular drivers of this resistance remain largely unknown.
- Idiopathic pulmonary fibrosis (IPF) represents a significant unmet medical need.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying myofibroblast apoptosis resistance in pulmonary fibrosis.
- To investigate the role of mesenchyme homeobox 1 (MEOX1) in PF progression.
- To identify potential therapeutic targets for mitigating PF.
Main Methods:
- Analysis of MEOX1 expression in IPF patient lungs and a mouse model of PF.
- In vitro studies using transforming growth factor-β1 (TGF-β1)-induced myofibroblasts.
- Gene silencing techniques to assess MEOX1 function.
- Bioinformatics analysis to identify downstream targets of MEOX1.
Main Results:
- MEOX1 expression is significantly elevated in PF lungs and TGF-β1-treated myofibroblasts.
- Silencing MEOX1 reduces PF progression in mice and enhances myofibroblast apoptosis.
- RGS4 was identified as a direct downstream target of MEOX1.
- MEOX1 confers apoptosis resistance in myofibroblasts via upregulation of RGS4.
Conclusions:
- Mesenchyme homeobox 1 (MEOX1) plays a critical role in myofibroblast apoptosis resistance during pulmonary fibrosis.
- MEOX1 promotes PF by upregulating G-protein signaling pathway regulatory factor 4 (RGS4).
- MEOX1 represents a promising therapeutic target for treating pulmonary fibrosis.
