FoxO1 Deficiency in M‐MDSCs 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. Forkhead box protein O1 (FoxO1) expression in monocytic MDSCs (M‐MDSCs) exhibits a negative correlation with the SLE Disease Activity Index (SLEDAI) score. This study aimed to investigate the hypothesis that M‐MDSCs specific FoxO1 deficiency enhances aberrant B cell function in aggressive SLE. Methods We used GEO datasets and clinical cohorts to verify the FoxO1 expression and circulating M‐MDSCs clinical significance. 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 ChIP‐seq with transcriptomic analysis, luciferase reporter assay and ChIP‐qPCR. Methylated RNA immunoprecipitation sequencing, RNA sequencing and CRISPR‐dCas9 were used to identify m 6 A modification. In vitro B cell co‐culture experiments, Capmatinib intragastric administration, m 6 A‐modulated MDSCs adoptive transfer, and SLE patient sample validation 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 SLE patients and lupus mice, and mice with myeloid FoxO1 deficiency (m FoxO1 ‐/‐ ) are more prone to B cell dysfunction. Mechanically, FoxO1 inhibits Met transcription by binding to the promoter region. M‐MDSCs FoxO1 deficiency blocks the Met/COX2/PGE2 secretion pathway, promoting B cell proliferation and hyperactivation. Met antagonist Capmatinib effectively mitigates lupus exacerbation. Furthermore, ALKBH5 targeting catalyzes m 6 A modification on FoxO1 mRNA in CDS and 3'‐UTR regions. Upregulation of FoxO1 mediated by ALKBH5 overexpression in M‐MDSCs improves lupus progression. Finally, these correlations were confirmed in untreated SLE patients. Conclusion Our findings indicate that effective inhibition of B cells mediated by ALKBH5/FoxO1/Met axis in M‐MDSCs could offer a novel therapeutic approach to manage SLE. image