<p>The abnormal activation and differentiation of B cells play an important role in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE). Alpha-ketoglutarate (α-KG), a key metabolite in the tricarboxylic acid cycle, has been shown to be involved in the pathogenesis of many diseases by regulating the immune response. However, the role of α-KG in the pathogenesis of SLE, as well as the activation and differentiation of B cells, remains unclear. In this study, we used organic acid-targeted metabolomics to analyze the changes in the levels of 100 organic acids in the serum of SLE patients and healthy controls, and found a significant increase in the α-KG level in SLE patients compared to that in healthy controls. Notably, α-KG significantly could inhibit the activation and differentiation of B cells and alleviate disease progression in lupus-prone mice. Mechanistically, RNA-seq revealed that α-KG upregulated the expression of ENTPD1, which encodes an important immune checkpoint molecule CD39; B-cell-specific loss of ENTPD1 could significantly promote the Toll-like receptors-mediated activation and differentiation of B cells and aggravate the disease conditions of lupus-prone mice. The findings of our study demonstrate that α-KG alleviates the pathogenesis of lupus and inhibits the activation and differentiation of B cells by increasing the expression of CD39. Our findings laid a theoretical foundation for understanding the pathogenesis of SLE. Based on our study, α-KG might be further examined as a drug for the effective treatment of SLE.</p>