PURPOSE: Ertugliflozin is a potent, selective, and orally active inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2), which is beneficial to cardiovascular health. We aimed to study the effect of Ertugliflozin on atherosclerosis (AS) in nondiabetic ApoE mice. METHODS: Eight-week-old apolipoprotein E knockout (ApoE) mice were randomly divided into two groups. Control group mice were fed high-fat diet (HFD), and the experimental group was fed HFD combined with Ertugliflozin (3.075 μg/g/d). Three months later, blood samples from all mice were collected to detect serum low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDLC). Aortic arch plaques were used for the assessment of plaque burden by hematoxylin-eosin staining (H&E staining). The relative lipid and macrophage contents of atherosclerotic plaques in two groups were assessed using Oil Red O staining and immunohistochemistry with an anti-MOMA2 (monocyte/macrophage) antibody. In the cell experiment, RAW264.7 cells were divided into 3 groups: a control group, induced with oxidized LDL (ox-LDL) group (50 μg/ml), and induced with ox-LDL combined with Ertugliflozin group (100 μM). Lipid accumulation was evaluated by Oil Red O staining; several adipogenesis markers were analyzed by real-time quantitative PCR (RT-qPCR) and western blotting (WB). Later, a specific inhibitor of this pathway (GW9662, 10 μM) was used to block its effect. The genes and proteins identified to be involved in this pathway were verified using RT-qPCR and WB. RESULTS: Ertugliflozin reduces lipid accumulation and arterial plaque formation in nondiabetic ApoE mice. H&E staining and Oil Red O staining of the two groups of mouse tissues indicated that the degree of AS in experimental mice was reduced, and the lipid components within the plaques were diminished following Ertugliflozin intervention. Histological staining showed plaque size in mouse aortic arch and abdominal aorta sections. Additionally, immunohistochemistry revealed that the expression of MOMA2 in the experimental mice plaques was significantly lower compared to that in the HFD group, suggesting that the plaques in the experimental mice were more stable. In vitro, Ertugliflozin upregulated the expression of low density lipoprotein receptor (LDLR) and ATP-binding cassette transporterA1 (ABCA1), upregulated the activity of the peroxisome proliferators-activated receptor γ/liver X receptor α (PPARγ/LXRα) pathway and downregulated the expression of cluster of differentiation 36 (CD36). When the PPARγ inhibitor (GW9662, 10 μM) was used to block the pathway, the effects of Ertugliflozin were also weakened. CONCLUSIONS: In summary, our results indicated that Ertugliflozin not only may reduce the area of atherosclerotic plaques in ApoE mice but also upregulate ABCA1 and LDLR via the PPARγ/LXRα pathway to play a role in macrophages. Ertugliflozin upregulates ABCA1 and LDLR via the PPARγ/LXRα pathway to hinder the formation of macrophage-derived foam cells and reduce MOMA2 expression in atherosclerotic plaques. Overall, our study reveals the potential medicinal value of Ertugliflozin in the treatment of AS, which provides a rationale for the use of Ertugliflozin in the clinical treatment of AS.