Single-cell multiomics uncovers an endothelial mechanosensitive PIEZO1-IL-33 axis driving pulmonary fibrosis.

Summary

Integrated single-cell multi-omics from human pulmonary fibrosis and mouse models revealed endothelial PIEZO1 upregulation as a hallmark of fibrosis. Endothelial-specific Piezo1 knockout attenuated bleomycin-induced fibrosis, and mechanistic studies linked PIEZO1 activation to CAPN2-mediated STAT3 phosphorylation and IL-33 secretion, nominating the endothelial PIEZO1–CAPN2–STAT3–IL-33 axis as a therapeutic target.

Key Findings

• Endothelial PIEZO1 is upregulated in human pulmonary fibrosis and in experimental bleomycin/silica models.
• Endothelial-specific Piezo1 knockout significantly attenuates bleomycin-induced fibrotic remodeling in mice.
• Mechanistically, PIEZO1 activation drives CAPN2-mediated STAT3 phosphorylation and regulates IL-33 secretion, promoting fibrosis.

Clinical Implications

The endothelial PIEZO1–IL-33 axis offers multiple points for intervention (PIEZO1, CAPN2, STAT3, IL-33) and suggests endothelial mechanosensing biomarkers could stratify progression or therapeutic response in pulmonary fibrosis.

Limitations

• Preclinical nature limits immediate clinical translation and safety/efficacy assessments.
• Sex-specific effects were not fully explored beyond mention of male mice in the abstract.
• Pharmacologic targetability of PIEZO1/CAPN2 in the lung requires validation.

Future Directions

Develop and test selective PIEZO1, CAPN2, STAT3, or IL-33 modulators in pulmonary fibrosis models and explore endothelial mechanosensing biomarkers in clinical cohorts.