{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T03:48:19Z","timestamp":1793936899251,"version":"4.8.0"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:00:00Z","timestamp":1750896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The fat mass and obesity-associated protein (FTO), a key RNA N<jats:sup>6<\/jats:sup>-methyladenosine (m<jats:sup>6<\/jats:sup>A) demethylase, has been highlighted for its important role in inflammatory response. Emerging evidences link the O-GlcNAcylation to numerous human diseases, particularly inflammation. However, the specific role and underlying mechanism of FTO O-GlcNAcylation in inflammation remain elusive.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The FTO O-GlcNAcylation modification was determined by co-immunoprecipitation (Co-IP) assay, metabolic glycan labeling combined with click reaction, and liquid chromatography-tandem mass spectrometry (LC-MS\/MS) analysis. Chromatin immunoprecipitation (ChIP)-qPCR and dual-luciferase reporter assay were used to determine FOXO1 binding to the <jats:italic>Gfat<\/jats:italic>2 promoter and the <jats:italic>Gfat<\/jats:italic>2 promoter activity during LPS stimulation. The FTO ubiquitination modification and the interaction between FTO and TRIM21 were detected by confocal microscopy, pull-down, and mass spectrometry analysis. The effects of FTO O-GlcNAcylation on the ubiquitination degradation of FTO were assessed by Co-IP and protein stability assays. The <jats:italic>Socs<\/jats:italic>1 mRNA m<jats:sup>6<\/jats:sup>A methylation levels were detected by m<jats:sup>6<\/jats:sup>A-RNA-immunoprecipitation (RIP)-qPCR. The myeloid-specific <jats:italic>Fto<\/jats:italic> deletion (mye<jats:italic>Fto<\/jats:italic><jats:sup>-\/-<\/jats:sup>) mice, the macrophage depletion and reconstitution experiments, and enzyme-linked immunosorbent assays (ELISA) were used to evaluate inflammatory responses in <jats:italic>Salmonella Typhimurium<\/jats:italic> (<jats:italic>S. Typhimurium<\/jats:italic>) or bacterial endotoxin (lipopolysaccharide, LPS) induced sepsis mouse models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrate that FTO undergoes O-GlcNAcylation specifically at the serine 95 (Ser95) site. LPS enhances FTO O-GlcNAcylation modification levels by increasing the FOXO1-regulated GFAT2 expression. O-GlcNAcylation of FTO promotes TRIM21-mediated K48-ubiquitination degradation of FTO, which further induces suppressor of cytokine signaling (<jats:italic>Socs<\/jats:italic>) 1 m<jats:sup>6<\/jats:sup>A methylation, thus sustains SOCS1 protein expression and suppresses multiple inflammatory cytokines IL-1\u03b2\/IL-6\/TNF-\u03b1 production in LPS-stimulated macrophages. FTO O-GlcNAcylation mutation (S95A) aggravates <jats:italic>S. Typhimurium<\/jats:italic> or LPS-induced sepsis, while FTO O-GlcNAcylation suppresses the hyperinflammatory phenotype in mice. Promotion of O-GlcNAcylation by an OGA inhibitor Thiamet-G alleviates LPS-induced inflammatory responses and septic shock in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings reveal a mechanism that FTO O-GlcNAcylation promotes its ubiquitination degradation, and thus induces <jats:italic>Socs1<\/jats:italic> m<jats:sup>6<\/jats:sup>A methylation and downregulates LPS-mediated inflammatory response, which maintains the negative feedback control of macrophage inflammatory cytokine storm in sepsis. Regulation of FTO O-GlcNAcylation may offer a potential therapeutic strategy for combating endotoxin-induced inflammatory disease and other FTO abnormal expression-associated diseases.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1593243","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T04:10:52Z","timestamp":1750911052000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["FTO O-GlcNAcylation promotes TRIM21-mediated FTO ubiquitination degradation to sustain the negative feedback control of macrophage inflammation"],"prefix":"10.3389","volume":"16","author":[{"given":"Lu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bi-Feng","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Lian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2005.03.016","article-title":"Endotoxin- or pro-inflammatory cytokine-induced sickness behavior as an animal model of depression: focus on anhedonia","volume":"29","author":"De La Garza","year":"2005","journal-title":"Neurosci Biobehav Rev"},{"key":"B2","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/nrmicro1068","article-title":"TLR4 and infectious disease diversity","volume":"3","author":"Miller","year":"2005","journal-title":"Nat Rev Microbiol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2024.0179","article-title":"International consensus criteria for pediatric sepsis and septic shock","volume":"331","author":"Schlapbach","year":"2024","journal-title":"Jama"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.4110\/in.2020.20.e23","article-title":"Biomarkers and associated immune mechanisms for early detection and therapeutic management of sepsis","volume":"20","author":"Trzeciak","year":"2020","journal-title":"Immune Netw"},{"key":"B5","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1016\/s1473-3099(15)70112-x","article-title":"Sepsis: a roadmap for future research","volume":"15","author":"Cohen","year":"2015","journal-title":"Lancet Infect Dis"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pathol.1.110304.100200","article-title":"Severe sepsis and septic shock: the role of gram-negative bacteremia","volume":"1","author":"Munford","year":"2006","journal-title":"Annu Rev Pathol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-024-07694-z","article-title":"Sepsis: key insights, future directions, and immediate goals. 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