BACKGROUND: Nobiletin has been found to improve lipopolysaccharide-induced abnormal activation of microglia, excessive release of inflammatory factors and redox imbalance. However, the specific mechanism is not fully understood. OBJECTIVE: To investigate the molecular mechanism by which nobiletin can inhibit lipopolysaccharide-induced inflammation in BV2 microglia. METHODS: Passage 3 BV2 microglia were divided into three groups: control group was cultured for 24 hours (without any treatment). Lipopolysaccharide group was treated with 10 μg/mL lipopolysaccharide for 24 hours. Lipopolysaccharide + nobiletin group was treated with 20 μmol/L nobiletin for 6 hours and then 10 μg/mL lipopolysaccharide for 24 hours. After the processing, cell proliferation was detected by CCK-8 assay. The level of intracellular reactive oxygen species was detected by fluorescent probe. The mRNA expression levels of nuclear factor κB p65, tumor necrosis factor α, and interleukin-1β were detected by qRT-PCR. The protein expression levels of nuclear factor κB p65, p-nuclear factor κB p65, tumor necrosis factor α, and interleukin-1β were detected by western blot assay. RESULTS AND CONCLUSION: Compared with the control group, the proliferation activity of lipopolysaccharide group was decreased (P < 0.001). Compared with the lipopolysaccharide group, the cell proliferation activity of lipopolysaccharide + nobiletin group was increased (P < 0.001). Compared with the control group, the level of intracellular reactive oxygen species was increased in the lipopolysaccharide group (P < 0.001). Compared with the lipopolysaccharide group, the level of intracellular reactive oxygen species was decreased in the lipopolysaccharide + nobiletin group (P < 0.01). Compared with the control group, the mRNA expression levels of tumor necrosis factor α and interleukin-1β were increased in the lipopolysaccharide group (P < 0.001, P < 0.01). Compared with the lipopolysaccharide group, mRNA expression levels of tumor necrosis factor α and interleukin-1β were decreased in the lipopolysaccharide + nobiletin group (P < 0.01, P < 0.05). Compared with the control group, the protein expression levels of p-nuclear factor κB p65, tumor necrosis factor α, and interleukin1β in were increased the lipopolysaccharide group (P < 0.001). Compared with the lipopolysaccharide group, the expression of p-nuclear factor κB p65, tumor necrosis factor α, and interleukin-1β was decreased in the lipopolysaccharide + nobiletin group (P < 0.001). These findings suggest that nobiletin attenuates lipopolysaccharide-induced inflammatory response in BV2 microglia by suppressing nuclear factor-κB signaling pathway. [ABSTRACT FROM AUTHOR]