This study investigates the role of mitochondrial DNA (mtDNA) synthesis in macrophages and its impact on inflammation and atherosclerosis. The research shows that vascular cell adhesion molecule 1 (VCAM-1) triggers mtDNA synthesis in macrophages within atherosclerotic plaques, leading to increased inflammation and atherogenesis. Mechanistically, VCAM-1 activates C/EBPα, which binds to promoters of key mitochondrial biogenesis genes (Cmpk2 and Pgc1α), thereby increasing mtDNA synthesis. This mtDNA synthesis activates the STING pathway, promoting inflammation. In vivo experiments in Apoe-/- mice lacking Vcam1 in macrophages demonstrate reduced atherosclerotic plaque burden and improved inflammation. Downregulation of macrophage-specific VCAM-1 leads to decreased expression of LYZ1 and FCOR, which are involved in STING signaling. Additionally, VCAM-1 expression in human carotid plaque macrophages correlates with mitochondrial volume, oxidative DNA damage, and necrotic core area. The study highlights the importance of macrophage VCAM-1 in inflammation and atherogenesis, proposing a self-escalating pathway involving increased mtDNA synthesis.This study investigates the role of mitochondrial DNA (mtDNA) synthesis in macrophages and its impact on inflammation and atherosclerosis. The research shows that vascular cell adhesion molecule 1 (VCAM-1) triggers mtDNA synthesis in macrophages within atherosclerotic plaques, leading to increased inflammation and atherogenesis. Mechanistically, VCAM-1 activates C/EBPα, which binds to promoters of key mitochondrial biogenesis genes (Cmpk2 and Pgc1α), thereby increasing mtDNA synthesis. This mtDNA synthesis activates the STING pathway, promoting inflammation. In vivo experiments in Apoe-/- mice lacking Vcam1 in macrophages demonstrate reduced atherosclerotic plaque burden and improved inflammation. Downregulation of macrophage-specific VCAM-1 leads to decreased expression of LYZ1 and FCOR, which are involved in STING signaling. Additionally, VCAM-1 expression in human carotid plaque macrophages correlates with mitochondrial volume, oxidative DNA damage, and necrotic core area. The study highlights the importance of macrophage VCAM-1 in inflammation and atherogenesis, proposing a self-escalating pathway involving increased mtDNA synthesis.