FoxO1 Deficiency in Monocytic Myeloid‐Derived Suppressor Cells Exacerbates B Cell Dysfunction in Systemic Lupus Erythematosus

Objective Myeloid‐derived suppressor cells (MDSCs) contribute to the pathogenesis of systemic lupus erythematosus (SLE), in part due to promoting the survival of plasma cells. FoxO1 expression in monocytic MDSCs (M‐MDSCs) exhibits a negative correlation with the SLE Disease Activity Index score. This study aimed to investigate the hypothesis that M‐MDSC–specific FoxO1 deficiency enhances aberrant B cell function in aggressive SLE. Methods We used GEO data sets and clinical cohorts to verify the clinical significance of FoxO1 expression and circulating M‐MDSCs. Using Cre‐LoxP technology, we generated myeloid FoxO1 deficiency mice (m FoxO1 −/− ) to establish murine lupus–prone models. The transcriptional stage was assessed by integrating chromatin immunoprecipitation (ChIP)–sequencing with transcriptomic analysis, luciferase reporter assay, and ChIP–quantitative polymerase chain reaction. Methylated RNA immunoprecipitation sequencing, RNA sequencing, and CRISPR‐dCas9 were used to identify N 6 ‐adenosine methylation (m 6 A) modification. In vitro B cell coculture experiments, capmatinib intragastric administration, m 6 A‐modulated MDSCs adoptive transfer, and sample validation of patients with SLE were performed to determine the role of FoxO1 on M‐MDSCs dysregulation during B cell autoreacted with SLE. Results We present evidence that low FoxO1 is predominantly expressed in M‐MDSCs in both patients with SLE and lupus mice, and mice with myeloid FoxO1 deficiency (m FoxO1 −/− ) are more prone to B cell dysfunction. Mechanically, FoxO1 inhibits mesenchymal‐epithelial transition factor protein (Met) transcription by binding to the promoter region. M‐MDSCs FoxO1 deficiency blocks the Met/cyclooxygenase2/prostaglandin E 2 secretion pathway, promoting B cell proliferation and hyperactivation. The Met antagonist capmatinib effectively mitigates lupus exacerbation. Furthermore, alkB homolog 5 (ALKBH5) targeting catalyzes m 6 A modification on FoxO1 messenger RNA in coding sequences and 3' untranslated regions. The up‐regulation of FoxO1 mediated by ALKBH5 overexpression in M‐MDSCs improves lupus progression. Finally, these correlations were confirmed in untreated patients with SLE. Conclusion Our findings indicate that effective inhibition of B cells mediated by the ALKBH5/FoxO1/Met axis in M‐MDSCs could offer a novel therapeutic approach to manage SLE. image