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OBJECTIVE The objective of this study was to discuss the mechanism of artesunate (ART) in improving cartilage damage in osteoarthritis (OA) by regulating the expression levels of MTA1, LXA4, and the downstream JAK2/STAT3 signaling pathway. METHODS The OA model in vitro was constructed by stimulating chondrocytes for 24 h with 10 ng/mL IL-1β, and cell proliferation and apoptosis, expression levels of Aggrecan, MTA1, LXA4, MMP3, MMP13, and Collagen II, and inflammatory cytokines in the culture supernatants were examined. Histopathological changes, inflammatory response, and chondrocyte apoptosis of the cartilage tissues of OA mice were performed. RESULTS In vitro cell experiments, ART enhanced cell proliferation capacity, accompanied by decreased apoptosis rate, decreased expression of MMP-3 and MMP-13, elevated expression of Collagen II and Aggrecan, as well as reduced levels of IL-6 and TNF-α in the cell supernatant. ART also ameliorated IL-1β-induced chondrocyte damage by upregulating MTA1. The LXA4 promoter region had two potential binding sites for MTA1. There was a positive correlation between MTA1 and LXA4. MTA1 enhanced the expression of LXA4 through transcription and blocked the activation of the JAK2/STAT3 signaling pathway. In vivo animal model experiments further showed that ART treatment alleviated cartilage tissue damage in OA model mice by up-regulating MTA1. CONCLUSION Our study demonstrates that ART improves the cartilage damage of OA by up-regulating MTA1 expression and promoting the transcriptional activation of LXA4, and further blocking the JAK2/STAT3 signaling pathway.