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Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cognitive impairment that currently is uncurable. Previous study shows that trilobatin (TLB), a naturally occurring food additive, exerts neuroprotective effect in experimental models of AD. In the present study we investigated the molecular mechanisms underlying the beneficial effect of TLB on experimental models of AD in vivo and in vitro. APP/PS1 transgenic mice were administered TLB (4, 8 mg· kg -1 ·d -1 , i.g.) for 3 months; rats were subjected to ICV injection of Aβ 25-35 , followed by administration of TLB (2.5, 5, 10 mg· kg -1 ·d -1 , i.g.) for 14 days. We showed that TLB administration significantly and dose-dependently ameliorated the cognitive deficits in the two AD animal models, assessed in open field test, novel object recognition test, Y-maze test and Morris water maze test. Furthermore, TLB administration dose-dependently inhibited microglia and astrocyte activation in the hippocampus of APP/PS1 transgenic mice accompanied by decreased expression of high-mobility group box 1 (HMGB1), TLR4 and NF-κB. In Aβ 25-25 -treated BV2 cells, TLB (12.5-50 μM) concentration-dependently increased the cell viability through inhibiting HMGB1/TLR4/NF-κB signaling pathway. HMGB1 overexpression abrogated the beneficial effects of TLB on BV2 cells after Aβ 25-35 insults. Molecular docking and surface plasmon resonance assay revealed that TLB directly bound to HMGB1 with a K D value of 8.541×10 -4 M. Furthermore, we demonstrated that TLB inhibited Aβ 25-35 -induced acetylation of HMGB1 through activating SIRT3/SOD2 signaling pathway, thereby restoring redox homeostasis and suppressing neuroinflammation. These results, for the first time, unravel a new property of TLB: rescuing cognitive impairment of AD via targeting HMGB1 and activating SIRT3/SOD2 signaling pathway., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)