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

Summary

Using mouse ARDS-fibrosis models and epithelial cell systems, the authors show that MBD2 is upregulated during EMT and fibrosis, and its knockout or knockdown attenuates these processes. Mechanistically, MBD2 appears to regulate FZD2, linking epigenetic control to Wnt signaling and ARDS-related pulmonary fibrosis; scRNA-seq from ARDS and human fibrosis samples support translational relevance.

Key Findings

• MBD2 expression increases during EMT and fibrosis in murine BLM/LPS models; MBD2 knockout attenuates EMT and pulmonary fibrosis.
• TGF-β induces EMT with upregulation of MBD2 in alveolar epithelial cells; MBD2 knockdown mitigates, while overexpression exacerbates EMT.
• ChIP/RNA-Seq implicate FZD2 as an MBD2 target, linking epigenetic regulation to Wnt signaling in ARDS-related fibrosis.
• scRNA-seq from ARDS and human pulmonary fibrosis samples show elevated MBD2 in alveolar epithelium, supporting translational relevance.

Clinical Implications

While preclinical, the MBD2–FZD2 axis suggests a pathway for antifibrotic interventions after ARDS. Stratifying ARDS survivors at risk of fibrosis and testing MBD2 or FZD2 modulators could be clinically meaningful.

Limitations

• Preclinical study without interventional validation in humans
• Potential model-specific effects and lack of independent external replication

Future Directions

Test pharmacologic or genetic modulation of MBD2/FZD2 in large-animal models and early-phase human studies; longitudinal profiling in ARDS survivors to link MBD2 activity with fibrotic outcomes.