Piezo1 specific deletion in endothelial cell protects the progression of pulmonary fibrosis in mice.

BACKGROUND: Piezo1, a mechanosensitive cation channel, plays a pivotal role in the pathogenesis of fibrosis by promoting intracellular calcium ion (Ca(2+)) influx and activating the calcium-dependent cysteine protease calpain. Pulmonary fibrosis (PF) is a progressive and often incurable disease, with current treatment strategies primarily relying on antifibrotic agents to slow disease progression. Accumulating evidence suggests that interdiction of Piezo1-induced Ca(2+) signaling may suppress epithelial–mesenchymal transition (EMT) and modulate myofibroblast activation, thereby ameliorating PF. However, whether endothelial Piezo1 contributes to PF and the underlying mechanisms remain elusive. OBJECTIVES: This study aims to investigate the role of endothelial Piezo1 in mediating the development of PF. METHODS: A murine model of PF was established using bleomycin (BLM). Mice were sacrificed at 14 and 21 days post-administration. To investigate the role of Piezo1 in mediating endothelial–mesenchymal transition (EndMT) during PF, endothelial cell-specific Piezo1 knockout mice were generated. In parallel, in vitro experiments were conducted in which mesenchymal transition was induced by TGF-β1, followed by treatment with the Piezo1 activator Yoda1, the inhibitor GsMTx4 (a spider-venom peptide that blocks cationic mechanosensitive channels), and Piezo1-targeting siRNA to further validate the functional role of Piezo1. RESULTS: In this study, we found that endothelial-specific deletion of Piezo1 (Piezo1(ΔCDH5)) in a BLM-induced PF mouse model effectively alleviates lung injury by reducing fibrotic lesions. In both in vivo and in vitro experiments, endothelial Piezo1 knockout significantly inhibited EndMT. Phenotypically, Piezo1(ΔCDH5) mice exhibited markedly reduced PF and inflammation. Mechanistically, endothelial Piezo1 senses mechanical cues within the pulmonary microenvironment and opens to elicit Ca(2+) influx. The resultant rise in intracellular Ca(2+) activates calpain, which subsequently amplifies p38 and ERK phosphorylation, thereby driving EndMT and contributing to PF. CONCLUSIONS: Our findings demonstrate that Piezo1 regulates the p38/ERK-MAPK signaling pathway via the Ca(2+)/calpain axis to inhibit EndMT, thereby ameliorating PF. These results suggest that Piezo1 may serve as a potential therapeutic target for slowing the progression of PF. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-026-02758-7.