Severe and persistent endoplasmic reticulum （ER） stress generates a distinct activation state in astrocytes, promoting the progression of Alzheimer’s disease (AD). The overactivation of astrocytes contributes to neuroinflammation and further loss of neuronal function. Therefore, modulating astrocytic activation is a potential neuroprotective approach. We have recently found that artemisinin had significant neuroprotective effects. However, how artemisinin regulates astrocyte activation to improve AD processes remains to be explored. This study is aimed to investigate the effect of artemisinin on astrocyte reactivity and its underlying mechanisms, like such as the regulation of ER stress. Our data show showed that amyloid β-peptide 1-42 (Aβ1-42) induced ER stress and astrocyte reactivity in vitro and in vivo animal model 3×Tg-AD mice while artemisinin can significantly reverse the effect of Aβ1-42. Artemisinin inhibits the release of inflammatory cytokines but promotes the expression of neurotrophic factors, thereby increasing astrocyte neurotropism to prevent neuronal injury. Artemisinin inhibits the phosphorylation of IRE1 and the downstream TRAF2-mediated nuclear factor-kappa B (NF-κB) signaling pathway. It is worth noticing that the inhibitor of PP2A, which is a phosphatase of IRE1, can reverse the effect of artemisinin on IRE1 phosphorylation and downstream signaling. Therefore, our results indicate that Artemisinin attenuated Aβ1-42-induced astrocyte overactivation by inhibiting the IRE1/TRAF2 pathway. These findings suggest that artemisinin could be a potential and promising candidate drug for AD treatment. Supported by National Natural Science Foundation of China (32070969), The Science and Technology Development Fund, Macau SAR (File No. 0127/2019/A3, 0113/2018/A3 and 0038/2020/AMJ), The Guangdong Provincial Funding Committee for Basic and Applied Fundamental Research (2022-Natural Science Foundation), University of Macau (File No. MYRG2018-00134-FHS and MYRG2020-00158-FHS).

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