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FoxO1 expression in monocytic MDSCs (M\u2010MDSCs) exhibits a negative correlation with the SLE Disease Activity Index score. This study aimed to investigate the hypothesis that M\u2010MDSC\u2013specific FoxO1 deficiency enhances aberrant B cell function in aggressive SLE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used GEO data sets and clinical cohorts to verify the clinical significance of FoxO1 expression and circulating M\u2010MDSCs. Using Cre\u2010LoxP technology, we generated myeloid FoxO1 deficiency mice (m<jats:italic>FoxO1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) to establish murine lupus\u2013prone models. The transcriptional stage was assessed by integrating chromatin immunoprecipitation (ChIP)\u2013sequencing with transcriptomic analysis, luciferase reporter assay, and ChIP\u2013quantitative polymerase chain reaction. Methylated RNA immunoprecipitation sequencing, RNA sequencing, and CRISPR\u2010dCas9 were used to identify N<jats:sup>6<\/jats:sup>\u2010adenosine methylation (m<jats:sup>6<\/jats:sup>A) modification. In vitro B cell coculture experiments, capmatinib intragastric administration, m<jats:sup>6<\/jats:sup>A\u2010modulated MDSCs adoptive transfer, and sample validation of patients with SLE were performed to determine the role of FoxO1 on M\u2010MDSCs dysregulation during B cell autoreacted with SLE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We present evidence that low FoxO1 is predominantly expressed in M\u2010MDSCs in both patients with SLE and lupus mice, and mice with myeloid FoxO1 deficiency (m<jats:italic>FoxO1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) are more prone to B cell dysfunction. Mechanically, FoxO1 inhibits mesenchymal\u2010epithelial transition factor protein (Met) transcription by binding to the promoter region. M\u2010MDSCs FoxO1 deficiency blocks the Met\/cyclooxygenase2\/prostaglandin E<jats:sub>2<\/jats:sub> secretion pathway, promoting B cell proliferation and hyperactivation. The Met antagonist capmatinib effectively mitigates lupus exacerbation. Furthermore, alkB homolog 5 (ALKBH5) targeting catalyzes m<jats:sup>6<\/jats:sup>A modification on <jats:italic>FoxO1<\/jats:italic> messenger RNA in coding sequences and 3' untranslated regions. The up\u2010regulation of FoxO1 mediated by ALKBH5 overexpression in M\u2010MDSCs improves lupus progression. Finally, these correlations were confirmed in untreated patients with SLE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings indicate that effective inhibition of B cells mediated by the ALKBH5\/FoxO1\/Met axis in M\u2010MDSCs could offer a novel therapeutic approach to manage SLE.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art43046-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.43046","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T03:34:12Z","timestamp":1730691252000},"page":"423-438","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["<scp>FoxO1<\/scp> 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