MBD2 promotes epithelial-to-mesenchymal transition (EMT) and ARDS-related pulmonary fibrosis by modulating FZD2

  • Biochim Biophys Acta Mol Basis Dis. 2025 Mar 12;1871(5):167798. doi: 10.1016/j.bbadis.2025.167798.
Yang Zhou  1 ,  Guifang Yang  2 ,  Jiqiang Liu  2 ,  Shuo Yao  2 ,  Jingsi Jia  2 ,  Xianming Tang  2 ,  Xun Gong  2 ,  Fang Wan  2 ,  Ren Wu  3 ,  Zhenyu Zhao  4 ,  Hengxing Liang  5 ,  Linxia Liu  6 ,  Qimi Liu  6 ,  Shanshan Xie  7 ,  Xian Long  8 ,  Xudong Xiang  9 ,  Guyi Wang  10 ,  Bing Xiao  11
Affiliations
  • 1. Department of Emergency Medicine, The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University, Changsha, Hunan, China; Department of Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
  • 2. Department of Emergency Medicine, The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University, Changsha, Hunan, China.
  • 3. Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
  • 4. Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
  • 5. Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Thoracic Surgery, Guilin Hospital of the Second Xiangya Hospital of Central South University, Guilin, Guangxi, China.
  • 6. Department of Respiratory and Critical Care Medicine, Guilin Hospital of the Second Xiangya Hospital of Central South University, Guilin, Guangxi, China.
  • 7. Department of Emergency Medicine, Guilin Hospital of the Second Xiangya Hospital of Central South University, Guilin, Guangxi, China.
  • 8. Department of Clinic, Medicine School, Changsha Social Work College, Changsha, Hunan, China.
  • 9. Department of Emergency Medicine, The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University, Changsha, Hunan, China; Department of Respiratory and Critical Care Medicine, Guilin Hospital of the Second Xiangya Hospital of Central South University, Guilin, Guangxi, China.
  • 10. Department of Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China. Electronic address: [email protected].
  • 11. Department of Emergency Medicine, Guilin Hospital of the Second Xiangya Hospital of Central South University, Guilin, Guangxi, China; Department of Emergency Medicine, The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University, Changsha, Hunan, China. Electronic address: [email protected].
PMID: 40081619 DOI: 10.1016/j.bbadis.2025.167798
Abstract

Objective: To investigate the role and underlying mechanism of Methyl-CpG binding domain protein 2 (MBD2) in the pathogenesis of acute respiratory distress syndrome (ARDS)-related pulmonary fibrosis.

Methods: Murine models for ARDS-related pulmonary fibrosis were established in wildtype or MBD2 knockout mice, expressions of MBD2 were determined with immunohistochemistry (IHC), immunofluorescence, and western blot. Epithelial-to-mesenchymal transition (EMT) was detected with determined with decreased expression of E-cadherin and increased expressions of N-Cadherin, Vimentin, and α-smooth muscle actin (α-SMA). Transforming growth factor β (TGF-β) treated mouse lung epithelial-12 (MLE-12) cells and primary human type II alveolar epithelial cells were applied to establish in vitro model for EMT. Transcriptional Sequencing with RNA-Seq and Chromatin immunoprecipitation (ChIP) assay were used to explore the potential targets of MBD2. Single cell Sequencing data and Human pulmonary fibrosis samples were analyzed.

Results: Bleomycin (BLM) and lipopolysaccharide (LPS) induced EMT, pulmonary fibrosis, and increased expression of MBD2 in alveolar epithelial cells of mice, and MBD2 knockout significantly alleviated BLM- and LPS-induced pulmonary fibrosis and EMT. TGF-β induced EMT and elevated MBD2 expressions in alveolar epithelial cells, which was mitigated by MBD2 knockdown and aggravated by MBD2 overexpression. Frizzled 2 (FZD2) was found to be the potential target of MBD2. Single-cell Sequencing analysis of ARDS patients suggested elevated expression of MBD2 in alveolar epithelial cells, and MBD2 expression was elevated in the lungs of patients with pulmonary fibrosis.

Conclusion: Our results indicated that MBD2 could promote EMT and ARDS-related pulmonary fibrosis, potentially by modulating the expression of FZD2.

Keywords
Acute respiratory distress syndrome (ARDS); Alveolar epithelial cell; Epithelial-to-mesenchymal transition (EMT); FZD2; Methyl-CpG binding domain protein 2 (MBD2); Pulmonary fibrosis.
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