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Although lipid mediators are known to play dual roles in promoting and resolving inflammation, the lipid species governing the Th17\u2010neutrophil axis in NA remain unknown. Here, through integrated lipidomic profiling of clinical samples (exhaled breath condensate, plasma, sputum) from an NA cohort and a murine model of Th17\u2010driven airway inflammation, a deficiency in very\u2010long\u2010chain ceramides, notably Cer24:1, was identified. This reduction correlated with disease severity and neutrophilic inflammation. In vivo, Cer24:1 supplementation alleviated airway hyperresponsiveness and neutrophilic infiltration, while\n                    <jats:italic>Smpd1<\/jats:italic>\n                    knockout mice\u2014with impaired ceramide generation\u2014displayed exacerbated Th17 pathology. Using structure\u2010guided molecular docking, surface plasmon resonance, and functional assays, Cer24:1 was shown to directly target the prostaglandin E2 receptor EP2 on CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells. This interaction suppressed JAK2\u2013STAT3 signaling and ROR\u03b3t\u2010driven Th17 differentiation. Notably, PGE\n                    <jats:sub>2<\/jats:sub>\n                    competitively reversed Cer24:1's protective effects, further supporting EP2\u2010dependent modulation. Our results reveal Cer24:1 as an endogenous pro\u2010resolving lipid that constrains neutrophilic inflammation via direct modulation of the EP2\u2013STAT3 axis in Th17 cells, providing a new metabolic checkpoint and potential therapeutic strategy for severe neutrophilic asthma.\n                  <\/jats:p>","DOI":"10.1002\/advs.202520695","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T18:50:09Z","timestamp":1773427809000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Endogenous Ceramide 24:1 Constrains Th17\u2010Driven Neutrophilic Inflammation by Antagonizing EP2 Signaling"],"prefix":"10.1002","volume":"13","author":[{"given":"Huan","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine Peking University Third Hospital Beijing 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