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

Pulmonary fibrosis (PF) represents a progressive interstitial lung disease marked by excessive extracellular matrix deposition and architectural distortion. Vascular endothelial cells (ECs) critically contribute to fibrogenesis through paracrine secretion of pro-fibrotic mediators, yet their mechanobiological regulation remains elusive. UsingThrough integrated single-cell multi-omics profiling of human PF specimens and experimental fibrosis models induced by bleomycin or silica (Bleomycin/SiO2-induced), we identify identified mechanosensitive Piezo1 upregulation in ECs as a hallmark of fibrotic progression. Endothelial-specific Piezo1 knockout significantly attenuates attenuated Bleomycin-induced fibrotic remodeling, establishing its pathogenic necessity. Mechanistically, Piezo1 activation promotes promoted PF development by inducing a pro-fibrotic molecule interleukin-33 (IL-33) secretion via CAPN2-mediated STAT3 phosphorylation. These findings suggest that the endothelial PIEZO1-CAPN2-STAT3-IL-33 axis is a promising therapeutic target for PF intervention. Overall design: Human lung tissues were obtained from five Normal individuals and four IPF patients.