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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\n                      <jats:sup>2+<\/jats:sup>\n                      signaling may suppress epithelial\u2013mesenchymal transition (EMT) and modulate myofibroblast activation, thereby ameliorating PF. However, whether endothelial Piezo1 contributes to PF and the underlying mechanisms remain elusive.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This study aims to investigate the role of endothelial Piezo1 in mediating the development of PF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A murine model of PF was established using bleomycin (BLM). Mice were sacrificed at 14 and 21\u00a0days post-administration. To investigate the role of Piezo1 in mediating endothelial\u2013mesenchymal 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-\u03b21, 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In this study, we found that endothelial-specific deletion of\n                      <jats:italic>Piezo1<\/jats:italic>\n                      (\n                      <jats:italic>Piezo1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u0394CDH5<\/jats:italic>\n                      <\/jats:sup>\n                      ) in a BLM-induced PF mouse model effectively alleviates lung injury by reducing fibrotic lesions. In both in vivo and in vitro experiments, endothelial\n                      <jats:italic>Piezo1<\/jats:italic>\n                      knockout significantly inhibited EndMT. Phenotypically,\n                      <jats:italic>Piezo1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u0394CDH5<\/jats:italic>\n                      <\/jats:sup>\n                      mice exhibited markedly reduced PF and inflammation. Mechanistically, endothelial Piezo1 senses mechanical cues within the pulmonary microenvironment and opens to elicit Ca\n                      <jats:sup>2+<\/jats:sup>\n                      influx. The resultant rise in intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      activates calpain, which subsequently amplifies p38 and ERK phosphorylation, thereby driving EndMT and contributing to PF.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our findings demonstrate that Piezo1 regulates the p38\/ERK-MAPK signaling pathway via the Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \/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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12964-026-02758-7","type":"journal-article","created":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T03:35:42Z","timestamp":1772249742000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Piezo1 specific deletion in endothelial cell protects the progression of pulmonary fibrosis in mice"],"prefix":"10.1186","volume":"24","author":[{"given":"Bin","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaorui","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honglin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoting","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rentao","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youfen","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianmei","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintao","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangfei","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajuan","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"2758_CR1","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.rmed.2017.05.017","volume":"129","author":"G Raghu","year":"2017","unstructured":"Raghu G, Richeldi L. 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