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Fibroblast growth factor 15 (FGF15) suppresses septic inflammation through its FGF receptor 4 (FGFR4); however, the underlying mechanisms are largely unclear. In this study, we evaluated the anti-inflammatory effects of recombinant FGF15 (rFGF15) in cecal ligation and puncture (CLP)-induced septic mice in vivo, as well as lipopolysaccharide (LPS)-stimulated mouse bone marrow-derived macrophages (BMDMs) and RAW264.7 macrophages in vitro. We observed that rFGF15 suppressed M1 macrophage polarization and associated inflammatory responses in both CLP-induced septic mice and LPS-stimulated BMDMs and RAW264.7 macrophages. Additionally, macrophage-depleted CLP mice transplanted with LPS-stimulated BMDMs pre-treated with rFGF15 exhibited reduced multi-organ inflammation and enhanced survival compared to those receiving LPS-stimulated BMDMs without rFGF15 treatment. Mechanistically, FGF15 activated the neurofibromin 2 (NF2)-Hippo pathway through FGFR4, leading to the inhibition of glycolysis, lactate production, and histone H3K18 lactylation. This led to reduced expression of interferon regulatory factor 7 (Irf7), a key regulator of type I interferon responses. In conclusion, FGF15 suppresses M1 macrophage polarization and associated inflammatory responses in sepsis by activating the NF2-Hippo pathway, thereby inhibiting H3K18 lactylation-driven <jats:italic>Irf7<\/jats:italic> expression. FGF15 holds promise as a potential innovative therapy for sepsis.<\/jats:p>","DOI":"10.1038\/s41419-025-07962-w","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:16:02Z","timestamp":1755562562000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["FGF15\/FGFR4 signaling suppresses M1 macrophage polarization and multi-organ inflammation in septic mice by inhibiting H3K18 lactylation-driven Irf7 expression through NF2-Hippo activation"],"prefix":"10.1038","volume":"16","author":[{"given":"Bo","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zexiang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geshu","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5020-4584","authenticated-orcid":false,"given":"Xing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,19]]},"reference":[{"key":"7962_CR1","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","volume":"395","author":"KE Rudd","year":"2020","unstructured":"Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. 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