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However, the precise mechanistic understanding of how <jats:italic>P. multocida<\/jats:italic> disrupts the epithelial barrier in mammalian lung remains largely unknown. In this study, using unbiased RNA-seq analysis, we found that the evolutionarily conserved Hippo-Yap pathway was dysregulated after <jats:italic>P. multocida<\/jats:italic> infection. Given the complexity of <jats:italic>P. multocida<\/jats:italic> infection associated with lung injury and systemic inflammatory processes, we employed a combination of cell culture models, mouse models, and rabbit models to investigate the dynamics of the Hippo-Yap pathway during <jats:italic>P. multocida<\/jats:italic> infection. Our findings reveal that <jats:italic>P. multocida<\/jats:italic> infection activates the Hippo-Yap pathway both in vitro and in vivo, by upregulating the upstream factors p-Mst1\/2, p-Lats1, and p-Yap, and downregulating the downstream effectors <jats:italic>Birc5<\/jats:italic>, <jats:italic>Cyr61<\/jats:italic>, and <jats:italic>Slug<\/jats:italic>. Conversely, pharmacological inhibition of the Hippo pathway by XMU-MP-1 significantly rescued pulmonary epithelial cell apoptosis in vitro and reduced lung injury, systemic inflammation, and mouse mortality in vivo. Mechanistic studies revealed that <jats:italic>P. multocida<\/jats:italic> induced up-regulation of Rassf1 expression, and Rassf1 enhanced Hippo-Yap pathway through phosphorylation. Accordingly, in vitro knockdown of Rassf1 significantly enhanced Yap activity and expression of Yap downstream factors and reduced apoptosis during <jats:italic>P. multocida<\/jats:italic> infection. <jats:italic>P. multocida<\/jats:italic>-infected rabbit samples also showed overexpression of Rassf1, p-Lats1, and p-Yap, suggesting that <jats:italic>P. multocida<\/jats:italic> activates the Rassf1-Hippo-Yap pathway. These results elucidate the pathogenic role of the Rassf1-Hippo-Yap pathway in <jats:italic>P. multocida<\/jats:italic> infection and suggest that this pathway has the potential to be a drug target for the treatment of pasteurellosis.<\/jats:p>","DOI":"10.1186\/s13567-024-01285-y","type":"journal-article","created":{"date-parts":[[2024,3,16]],"date-time":"2024-03-16T10:01:54Z","timestamp":1710583314000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Pasteurella multocida activates Rassf1-Hippo-Yap pathway to induce pulmonary epithelial apoptosis"],"prefix":"10.1186","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0194-4604","authenticated-orcid":false,"given":"Guangfu","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhan","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiongli","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianci","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nengzhang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyi","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,16]]},"reference":[{"key":"1285_CR1","first-page":"1","volume":"361","author":"IW Wilkie","year":"2012","unstructured":"Wilkie IW, Harper M, Boyce JD, Adler B (2012) Pasteurella multocida: diseases and pathogenesis. 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