LAUSR

Neuroinflammation caused by neuroimmune dysfunction is important for the pathogenesis of major depressive disorders; new antidepressant treatments are urgently needed. Artemisinin (ART) has anti‐inflammatory and neuroprotective effects; it can alleviate the inflammatory response in the central nervous system. This study investigated the antidepressant effects and potential mechanisms of action of ART in mice with depression. Mice with chronic social defeat stress (CSDS) and lipopolysaccharide (LPS)‐induced depression were used to investigate the antidepressant effects and mechanisms of ART. Mice were treated with ART for 60 min or 5 days. Behavioral tests, RNA sequence analysis, molecular docking, immunofluorescence, and Western blotting were used to evaluate the antidepressant effects of ART as well as its potential therapeutic targets and signaling pathways. Additionally, LPS‐ and ATP‐treated BV2 microglia were analyzed in vitro to confirm the effect of ART on the NLRP3 signaling pathway. After 60 min or 5 days of treatment, ART alleviated depression‐like behavior in CSDS‐induced mice. RNA sequence analysis and molecular docking revealed that ART inhibited the TLR4/NLRP3 signaling pathway. After 5 days of treatment, ART suppressed CSDS‐induced microglia, astrocytes, and NLRP3 inflammasome activation as well as the expression of IL‐17A in the hippocampus. Mechanistically, ART markedly inhibited TLR4, MyD88, p‐NF‐κB, and NLRP3 inflammasome‐associated proteins in the hippocampus of CSDS‐induced mice. Furthermore, ART improved LPS‐induced depression‐like behavior by inhibiting the TLR4/NLRP3 signaling pathway. ART, a novel antidepressant with clinical potential, inhibits neuroinflammation by downregulating the TLR4/MyD88/NF‐κB/NLRP3 signaling pathway in the mouse hippocampus.