〔Abstract〕 Objective To investigate the effects and underlying mechanisms of α-mangostin in a spinal cord injury model of microglial cell inflammation. Methods Mouse microglial cell line BV-2 was culturedin vitro, and an inflammation model was established by co-treatment with lipopolysaccharide and adenosine triphosphate(LPS/ATP). The CCK-8 assay was used to test the influence of different concentrations(0, 10, 20, 40, 80 μmol/L) of α-mangostin on cell proliferation vitality under LPS/ATP stimulation to select an appropriate concentration range of α-mangostin; BV-2 cells were divided into Ctrl group, LPS/ATP group, 40 μmol/L α-mangostin group, and intervention groups with different concentrations(10, 20, 40 μmol/L) of α-mangostin(designated as LPS/ATP+10 μmol/L α-mangostin group, LPS/ATP+20 μmol/L α-mangostin group, and LPS/ATP+40 μmol/L α-mangostin group, respectively). ELISA experiments were conducted to detect the levels of pro-inflammatory cytokines interleukin-6/1β/18(IL-6, IL-1β, IL-18) and tumor necrosis factor(TNF-α) in the supernatants of each group, and Western blot was used to detect the expression of NLRP3, ASC, cleaved caspase-1, IL-1β, and the phosphorylation levels of p65(p-p65/p65) in the NF-κB pathway, as well as the expression of p65 in the nuclei of BV-2 cells. Results Compared with the Ctrl group, cell proliferation vitality in the LPS/ATP group was significantly reduced(P<0.05), but low concentrations(10, 20, 40 μmol/L) of α-mangostin significantly improved the inhibitory effect of LPS/ATP on microglial cell proliferation vitality(P<0.05), while a high concentration(80 μmol/L) of α-mangostin exacerbated the damage to microglial cells caused by LPS/ATP(P<0.05). Compared with the Ctrl group, the levels of inflammatory factors IL-6, IL-1β, IL-18, TNF-α, and the expression of NLRP3, ASC, cleaved caspase-1, IL-1β, and the p-p65/p65 ratio in the 40 μmol/L α-mangostin group, as well as the expression of p65 protein in the nuclei, showed no significant changes(P>0.05), whereas these significantly increased in the LPS/ATP group(P<0.05). Compared with the LPS/ATP group, the levels of IL-6, IL-1β, IL-18, TNF-α, and the expression of NLRP3, ASC, cleaved caspase-1, IL-1β, and the p-p65/p65 ratio in the intervention groups, as well as the expression of p65 protein in the nuclei, decreased in a concentration-dependent manner with increasing α-mangostin concentration, with the most significant reduction observed in the LPS/ATP+40 μmol/L α-mangostin group(P<0.01). Conclusion α-mangostin can inhibit the neuroinflammatory response mediated by NLRP3 inflammasome activation in BV-2 cells through the NF-κB pathway.