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Atherosclerotic plaque rupture is the major trigger of acute cardiovascular risk events, and manipulation of M1/M2 macrophage homeostasis is an effective strategy for regulating atherosclerotic plaque stability. This study was aimed to illuminate the effects of oleoylethanolamide (OEA) on macrophage polarization and plaque stability. Macrophages derived from THP-1 were treated with OEA followed by LPS/IFN-γ, and the markers of M1, M2 macrophages were monitored by western blot, real-time PCR and immunofluorescence staining. The effect of OEA on macrophage polarization in the arch of aortic arteries was tested by immunofluorescence staining and western blot, and the plaque stability was completed by Masson's trichrome and hematoxylin and eosin (HE) in apolipoprotein E (ApoE)−/− mice. OEA treatment enhanced the expression of two classic M2 macrophage markers, macrophage mannose receptor (CD206) and transforming growth factor (TGF-β), while the expression of iNOS (M1 macrophages) was decreased in THP-1-derived macrophages. Blocking of PPARα using siRNA and inhibition of AMP-activated protein kinase (AMPK) by its inhibitor compound C attenuated the OEA-induced expression of M2 macrophage markers. In addition, OEA significantly suppressed M1, promoted M2 macrophage polarization, increased collagen content and decreased necrotic core size in atherosclerotic plaques in ApoE−/− mice, which were linked with the expression of PPARα. OEA improved atherosclerotic plaque stability through regulating macrophage polarization via AMPK-PPARα pathway. • OEA suppressed macrophage M0 and M2 polarizing to M1. • OEA may switch M1 towards M2 macrophage. • OEA regulated macrophage polarization through the AMPK-PPARα pathway. • OEA improved plaque stability via regulating macrophage polarization in a AMPK-PPARα-dependent manner. [ABSTRACT FROM AUTHOR]