Paeonol could suppress atherosclerosis by inhibiting VSMCs proliferation via up-regulating autophagy through the AMPK/mTOR signaling pathway in vivo and in vitro. Our study offers novel insights into the anti-proliferation effect of Paeonol, which will provide references for clinic use of Paeonol for therapy of atherosclerosis. This evidence concerns the gene PRKAA1 and atherosclerosis.