AbstractPurposeThe aim of this study was to investigate the effect of dexmedetomidine (Dex) on inflammation and organ injury in sepsis, as well as the potential relationship between Dex and nuclear receptor 77 (Nur77).MethodsWe investigated the effects of dexmedetomidine on lipopolysaccharide (LPS)‐induced inflammation in RAW264.7 cells and organ injury in the cecal ligation and puncture (CLP) mouse model. Additionally, we examined the relationship between dexmedetomidine and Nur77. The expression levels of Nur77 in RAW264.7 cells were analyzed under various types of stimulation using quantitative reverse transcription polymerase chain reaction and western blot analysis. Inflammatory cytokine levels in the cells were evaluated using enzyme‐linked immunoassay. Organ injuries were assessed by examining tissue histology and pathology of the lung, liver, and kidney.ResultsDexmedetomidine increased the expression of Nur77 and IL‐10, and downregulated inflammatory cytokines (IL‐1β and TNF‐α) in LPS‐treated RAW264.7 cells. The effect of dexmedetomidine on inhibiting inflammation in LPS‐treated RAW264.7 cells was promoted by overexpressing Nur77, while it was reversed by downregulating Nur77. Additionally, dexmedetomidine promoted the expression of Nur77 in the lung and CLP‐induced pathological changes in the lung, liver, and kidney. Activation of Nur77 with the agonist Cytosporone B (CsnB) significantly suppressed the production of IL‐1β and TNF‐α in LPS‐treated RAW264.7 cells. In contrast, knockdown of Nur77 augmented IL‐1β and TNF‐α production in LPS‐treated RAW264.7 cells.ConclusionDexmedetomidine can attenuate inflammation and organ injury, at least partially, via upregulating Nur77 in sepsis.