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While alveolar macrophages and epithelial cells are recognized as critical mediators in ARDS pathogenesis, the molecular mechanisms underlying their dysfunction remain incompletely understood. This study investigated the regulatory role of the P2rx7\u2010Panx1 signaling axis in orchestrating alveolar macrophage pyroptosis and subsequent exosome\u2010mediated ferroptosis of alveolar epithelial cells in lipopolysaccharide (LPS)\u2010induced ARDS. The study utilized both an in\u00a0vivo ARDS mouse model and in\u00a0vitro systems comprising MH\u2010S alveolar macrophages and MLE\u201012 alveolar epithelial cells. P2rx7\u2010Panx1 interaction was characterized through Western blot analysis, immunofluorescence microscopy, and co\u2010immunoprecipitation studies. The functional consequences of P2rx7 and Panx1 depletion were assessed through comprehensive analyses of cell viability, inflammatory cytokine profiles, oxidative stress parameters, and protein expression patterns. LPS exposure induced significant upregulation and enhanced interaction of P2rx7 and Panx1 in alveolar macrophages both in\u00a0vivo and in\u00a0vitro. Selective knockdown of either P2rx7 or Panx1 significantly attenuated LPS\u2010induced macrophage pyroptosis, as evidenced by reduced cell death, diminished NLRP3\/ASC\/caspase\u20101 activation, and decreased IL\u20101\u03b2\/IL\u201018 secretion, with dual knockdown exhibiting synergistic protection. Furthermore, LPS\u2010stimulated macrophages induced ferroptosis in alveolar epithelial cells through P2rx7\u2010dependent exosome release, while P2rx7 blockade effectively prevented this exosome\u2010mediated epithelial cell ferroptosis. This study elucidates a novel mechanism whereby the P2rx7\u2010Panx1 axis synergistically regulates LPS\u2010induced alveolar macrophage pyroptosis through caspase\u201011\u2010dependent pathways. Moreover, P2rx7 functions as a critical modulator of exosome release from alveolar macrophages, thereby promoting ferroptotic death of alveolar epithelial cells. These findings identify the P2rx7\u2010Panx1 signaling axis as a promising therapeutic target in ARDS treatment.<\/jats:p>","DOI":"10.1096\/fj.202403385rr","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T12:56:57Z","timestamp":1755608217000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Synergistic Role of P2rx7 and Panx1 in Regulating Alveolar Macrophage Pyroptosis and Exosome\u2010Mediated Ferroptosis of Alveolar Epithelial Cells in Lipopolysaccharide\u2010Induced Acute Respiratory Distress Syndrome"],"prefix":"10.1096","volume":"39","author":[{"given":"Haiyan","family":"Rao","sequence":"first","affiliation":[{"name":"Department of Pediatrics the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University  Nanchang Jiangxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qunhua","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Abdominal Surgery Jiangxi Cancer Hospital  Nanchang Jiangxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University  Nanchang Jiangxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijun","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University  Nanchang Jiangxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2751-9558","authenticated-orcid":false,"given":"Jinghua","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University  Nanchang Jiangxi People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,19]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00439-6"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1608077"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","DOI":"10.1136\/bmj-2023-076612","article-title":"Acute Respiratory Distress Syndrome","volume":"387","author":"Wick K. 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