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In this study, we identify S100A9 as a macrophage\u2010derived alarmin that is markedly elevated in CRSwNP tissues. Integrative analyses of public bulk transcriptomic datasets and single\u2010cell RNA\u2010sequencing atlases demonstrated that S100A9 expression was predominantly enriched in macrophage clusters, where it showed strong co\u2010expression with canonical M1\u2010associated markers, while exhibiting limited expression in epithelial cell subsets. Spatial and correlation analyses further supported a close association between S100A9\u207a macrophages and epithelial barrier\u2013related gene signatures. Functionally, shRNA\u2010mediated silencing of S100A9 attenuated M1\u2010like macrophage polarization, as evidenced by reduced expression of pro\u2010inflammatory mediators and polarization markers, accompanied by a shift toward a less inflammatory macrophage phenotype. Conditioned media derived from S100A9\u2010deficient macrophages significantly mitigated epithelial injury, leading to restoration of epithelial barrier integrity, as indicated by enhanced expression of tight junction proteins, including occludin and claudins. Importantly, S100A9 knockdown disrupted the pathogenic macrophage\u2013epithelial inflammatory feedback loop, thereby dampening sustained inflammatory signaling and limiting epithelial barrier breakdown that perpetuates tissue damage in CRSwNP. Clinically, elevated S100A9 levels correlated with disease severity indices and effectively distinguished a macrophage\u2010enriched inflammatory endotype of CRSwNP, highlighting S100A9 as both a mechanistic driver and a potential biomarker for disease stratification. Collectively, these findings position S100A9 as a mechanistic mediator and a promising therapeutic target for CRSwNP.<\/jats:p>","DOI":"10.1111\/1348-0421.70060","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T06:51:17Z","timestamp":1778136677000},"page":"333-345","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Inflammatory Alarmin S100A9 Modulates Activation of Pro\u2010Inflammatory Macrophage to Protect Nasal Epithelial Cells From LPS\u2010Induced Epithelial\u2013Mesenchymal Transition"],"prefix":"10.1111","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3403-8093","authenticated-orcid":false,"given":"Yunxiang","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology\u2010Head and Neck Surgery, Huashan Hospital Fudan University Shanghai 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