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The abnormalities in cranial suture progenitor cells (SPC) are considered a key event in craniosynostosis; however, the specific mechanism remains unclear. Using a syndromic craniosynostosis mouse model, we found that hyperactivation of p38\u03b1 mitogen-activated protein kinase (MAPK) induced senescence in SPC of craniosynostosis mice. Integrated analysis of datasets from human patients and murine models, combined with cellular validation, revealed that p38\/p53 activation and cellular senescence were prevalent across multiple forms of craniosynostosis and corresponding experimental models. Additionally, senescent cells significantly promoted osteogenic differentiation of SPC by paracrine Tgf-\u03b21. Through in vivo and in vitro experiments, our evidence demonstrates that pharmacological inhibition of p38 MAPK, conditional knockout of\n                    <jats:italic>Mapk14<\/jats:italic>\n                    , and scAAV-mediated shRNA knockdown differentially attenuate SPC senescence, suture fusion, and elevated intracranial pressure, while ameliorating behavioral abnormalities in craniosynostosis mouse model. The present study supports p38\u03b1 MAPK as potential therapeutic target for craniosynostosis.\n                  <\/jats:p>","DOI":"10.1038\/s42003-025-09350-8","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T15:55:24Z","timestamp":1765641324000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["P38\u03b1 MAPK-induced senescence in cranial suture progenitor cells promotes craniosynostosis"],"prefix":"10.1038","volume":"9","author":[{"given":"Zong","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyou","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Yue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueying","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoshuang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenzhi","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guodong","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9350-7916","authenticated-orcid":false,"given":"Xiaolei","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,13]]},"reference":[{"key":"9350_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/01.prs.0000305929.40363.bf","volume":"121","author":"JA Persing","year":"2008","unstructured":"Persing, J. 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