Background and Purpose: Atherosclerosis is an underlying cause of coronary heart 
disease. Foam cell, a hallmark of atherosclerosis, is prominently derived from 
monocyte-differentiated macrophage, and vascular smooth muscle cells (VSMCs) 
through unlimitedly phagocytizing oxidized low-density lipoprotein (oxLDL). 
Therefore, the inhibition of monocyte adhesion to endothelium and uptake of 
oxLDL might be a breakthrough point for retarding atherosclerosis. Formononetin, 
an isoflavone extracted from Astragalus membranaceus, has exhibited multiple 
inhibitory effects on proatherogenic factors, such as obesity, dyslipidemia, and 
inflammation in different animal models. However, its effect on atherosclerosis 
remains unknown. In this study, we determined if formononetin can inhibit 
atherosclerosis and elucidated the underlying molecular mechanisms. Methods: 
ApoE deficient mice were treated with formononetin contained in high-fat diet 
for 16 weeks. After treatment, mouse aorta, macrophage and serum samples were 
collected to determine lesions, immune cell profile, lipid profile and 
expression of related molecules. Concurrently, we investigated the effect of 
formononetin on monocyte adhesion, foam cell formation, endothelial activation, 
and macrophage polarization in vitro and in vivo. Results: Formononetin reduced 
en face and aortic root sinus lesions size. Formononetin enhanced lesion 
stability by changing the composition of plaque. VSMC- and macrophage-derived 
foam cell formation and its accumulation in arterial wall were attenuated by 
formononetin, which might be attributed to decreased SRA expression and reduced 
monocyte adhesion. Formononetin inhibited atherogenic monocyte adhesion and 
inflammation. KLF4 negatively regulated the expression of SRA at transcriptional 
and translational level. Conclusions: Our study demonstrate that formononetin 
can substantially attenuate the development of atherosclerosis via regulation of 
interplay between KLF4 and SRA, which suggests the formononetin might be a novel 
therapeutic approach for inhibition of atherosclerosis.