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Emerging evidence suggests that Lipoxin A4 (LXA4) modulates macrophage immune responses. However, the precise role of LXA4 in regulating macrophage function in BPD and its underlying mechanisms remains unclear. Neonatal rats were exposed to 85% hyperoxia to establish a BPD model. LXA4 or M2\u2010polarized macrophage\u2010derived exosomes (M2\u2010exo) were injected intraperitoneally, and pulmonary inflammation, macrophage polarization and pyroptosis were examined. M2\u2010exo were co\u2010cultured with type II alveolar epithelial cells (AT2) to further validate the animal experimental findings and explore underlying mechanisms. Here, we find that monocyte\u2010derived\u00a0macrophages were activated in BPD. LXA4 significantly ameliorated lung tissue injury and pyroptosis by promoting M2\u2010exos release. Single\u2010cell transcriptomic profiling revealed altered macrophage\u2010epithelial cell interactions in BPD lungs. Mechanistic studies demonstrated that M2\u2010exo\u2010derived miR\u201025\u20105p alleviated AT2 pyroptosis, which targeted nuclear receptor binding protein 2 (NRBP2) and downregulated the PI3K\/AKT pathway. Additionally, PI3K inhibition (LY294002) or miR\u201025\u20105p knockdown reversed these protective effects. This study proved that LXA4 promotes M2 macrophage polarization and enhances exosomal miR\u201025\u20105p release, thereby inhibiting pyroptosis via the NRBP2\/PI3K\/AKT axis and ameliorating BPD lung injury. These findings elucidate the lung\u2010protective mechanism of LXA4 and highlight a novel macrophage\u2013AT2 cross\u2010talk in BPD, providing new therapeutic strategies for BPD\u2010related lung injury.<\/jats:p>","DOI":"10.1096\/fj.202500548rrr","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T16:50:53Z","timestamp":1762966253000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Lipoxin\n                    <scp>A4<\/scp>\n                    Regulates\n                    <scp>M2<\/scp>\n                    Macrophage\u2010Derived Exosomal\n                    <scp>miR<\/scp>\n                    \u201025\u20105p to Protect Cell Pyroptosis in Bronchopulmonary Dysplasia"],"prefix":"10.1096","volume":"39","author":[{"given":"Tianyu","family":"Chen","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital with Nanjing Medical University  Nanjing 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