Atherosclerosis is the most common cause of cardiovascular diseases, such as myocardial infarction and stroke.The aim of this study was to investigate the effects of a novel compound ZBM30 on atherosclerosis in ApoEdeficient mice and its associated mechanism.ApoEdeficient mice (6 weeks old), fed an atherogenic highfat and high cholesterol diet for 8 weeks, were divided into three groups.Two groups were orally administrated ZBM30(10, 30 mg· kg1) daily for 12 weeks, while the control group was administered saline.Atherosclerotic lesions with en face aortas were evaluated by Sudan V staining, and lesion areas in aortic sinuses were evaluated by oil red O staining.Necrotic core areas and fibrous cap areas in the lesion were evaluated by hematoxylin and eosin (HE)staining and Masson s trichrome staining in the aorta sinuses.The effects of ZBM30 on cholesterol accumulation in macrophages and cholesterol transporters: ATP binding cassette A1 (ABCA1) and ATP binding cassette G1 (ABCG1) were evaluated by oil red O assay, 3Hcholesterol efflux assay, Western blot, and realtime PCR on macrophage cell lines: Raw 264.7 and THP1.Immunofluoresces was used to determine the ABCA1 expression in macrophage in aorta sinuses.Luciferase reporters of wild type and mutant types of ABCA1 promoter were constructed to determine the regulatory domain of ZBM30 on ABCA1 promoter.Results showed that, compared with the control group, en face lesions in ZBM30 group (10, 30 mg · kg1) were reduced 54.96 ± 10.06% and 71.50 ± 15.37%respectively, and aorta sinus lesions were reduced 41.85 ± 11.21% and 82.23 ± 8.25% respectively.Necrotic core areas in the ZBM30 group were markedly reduced and fibrous cap areas were not changed.Oil red O staining and 3Hcholesterol efflux assays on Raw 264.7 cell line revealed that ZBM30 significantly attenuated the cholesterol accumulation in macrophages by enhancing apolipoprotein AI and HDL mediated cholesterol efflux.Furthermore,ZBM30 induced the protein and mRNA expression of cholesterol transporters such as ABCA1 and ABCG1.Immunofluoresces experiment revealed that ZBM30 induced the ABCA1 expression in macrophage in the lesion, which is consistent with the results in vitro.Luciferase reporter assay revealed that ZBM30 exerted its effect on ABCA1 via liver X receptor (LXR) binding domain.In conclusion, ZBM30 suppresses atherosclerosis through upregulating cholesterol efflux via ABCA1 and ABCG1 transporters in ApoEdeficient mice.