Inhibition of epithelial cell YAP-TEAD/LOX signaling attenuates pulmonary fibrosis in preclinical models.

Summary

Fibrotic AT2 cells drive matrix production and crosslinking through YAP-induced LOX. Pharmacologic YAP inhibition with verteporfin reverses AT2 reprogramming and LOX expression in murine fibrosis and human ex vivo tissue, nominating epithelial YAP-TEAD/LOX as a druggable IPF pathway.

Key Findings

• Fibrotic alveolar type II cells upregulate LOX via YAP, increasing extracellular matrix crosslinking.
• Verteporfin-mediated YAP inhibition reverses AT2 reprogramming and reduces LOX expression in vivo and in human fibrotic tissue ex vivo.
• Identifies epithelial YAP-TEAD/LOX signaling as a therapeutic axis for IPF.

Clinical Implications

Supports repurposing verteporfin and development of YAP-TEAD/LOX inhibitors targeting alveolar epithelium as potential disease-modifying therapies in IPF.

Limitations

• Preclinical evidence without clinical efficacy data in IPF patients.
• Potential off-target or photodynamic effects of verteporfin require careful clinical evaluation.

Future Directions

Phase 1/2 trials of verteporfin or selective YAP-TEAD/LOX inhibitors in IPF, biomarker development (epithelial YAP/LOX signatures), and safety profiling.