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Although the previous trials of inflammation have indicated that morin hydrate (MO) hold considerable promise, understanding the distinct mechanism of MO against inflammation remains a challenge.This study investigated the effect of MO in atherosclerosis in ApoE−/− mice and underlying cell signaling of MO effect in inflammation in human umbilical vein endothelial cells (HUVECs). Administration of MO significantly reduced serum lipid level, inflammatory cytokines (TNF-α and ICAM-1), and atherosclerotic plaque formation in vivo. MO presence attenuated the expression of TNF-α-induced inflammatory cytokines (ICAM-1, COX-2, and MMP-9), and remarkably enhanced microtubule associated protein 1 light chain 3 beta 2 (MAP1LC3B2) expression and sequestosome 1 (SQSTM1/p62) degradation in HUVECs. These MO effects were significantly prevented by the presence of autophagic inhibitors, 3-methyladenine (3-MA), or chloroquine (CQ), as well as siRNA suppression of ATG5 and BECN1. MO increased intracellular cAMP levels and activated cAMP-PKA-AMPK-SIRT1 signaling in vivo and in vitro. These changes resulted in increased expression of autophagy-related protein MAP1LC3B2 and decreased secretion of inflammatory cytokines (ICAM-1, COX-2, and MMP-9).Our results suggest that anti-AS and anti-inflammatory effects of MO are largely associated with its induction of autophagy through stimulation of cAMP-PKA-AMPK-SIRT1 signaling pathway.