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Sepsis is a life‐threatening disease characterized by multiple organ dysfunction. B cells play a pivotal role in sepsis. Here, we first observed the significantly reduced Flot2 gene expression in B cells from patients with bacterial sepsis and endotoxin‐induced septic mice. However, the effects of Flot2 on sepsis and B‐cell immunity remain unknown. Thus, we sorted B cells from Flot2 knockout (Flot2−/−) mice, RNA‐seq revealed significantly upregulated effector B cell (Beff) cytokines such as Il6, Il1b and Cxcl10 after Flot2 deficiency, while it showed no effect on the expression of regulatory B cell (Breg) cytokines such as Il10, Tgfb. Consistently, elevated Beff cytokine IL‐6 and unchanged Breg cytokine IL‐10 were shown in B cells from Flot2−/− mice. Similar results were subsequently observed in B cell‐specific Flot2 knockout chimeric mice. Notably, Flot2 deficiency aggravated sepsis with increased lung injury and shortened survival time in vivo by facilitating Beffs but not Bregs. Taken together, our data identify Flot2 as a novel controller of B cells, Flot2 deficiency amplifies inflammation by affecting Beffs to participate in the pathogenesis and progression of sepsis. [ABSTRACT FROM AUTHOR]