BACKGROUND: Calcific aortic valve disease (CAVD) leads to valve thickening and calcification. Valvular interstitial cells (VICs) play a crucial role in valve homeostasis and their differentiation into osteoblast-like cells is influenced by macrophages. Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in lipid metabolism and inflammation, but its role in CAVD remains unclear. METHODS: We evaluated TREM2 expression in CAVD using public datasets and clinical aortic valve samples. To investigate the impact and underlying mechanisms of macrophage TREM2 on VIC osteogenic differentiation, we utilized a high-fat diet (HFD)-induced ApoE RESULTS: TREM2 expression was significantly elevated in macrophages within calcified aortic valve tissues from CAVD patients, as determined by bioinformatics, flow cytometry, qRT-PCR, western blot, and immunofluorescence. Inhibition of TREM2 in ApoE CONCLUSION: TREM2 regulates macrophage oxidative phosphorylation, NLRP3 inflammasome activation, pyroptosis, and inflammatory responses through the PI3K/AKT pathway. This underscores TREM2 as a potential therapeutic target for mitigating aortic valve calcification and slowing the progression of CAVD.