Mitochondrial DNA (mtDNA) synthesis in macrophages is linked to inflammation and atherosclerosis. This study shows that vascular cell adhesion molecule 1 (VCAM-1) in atherosclerotic plaque macrophages promotes mtDNA synthesis, which activates the STING pathway and exacerbates inflammation and atherosclerosis. VCAM-1 activates C/EBPα, which enhances the expression of key mitochondrial biogenesis genes, leading to increased mtDNA synthesis. This process is associated with higher mitochondrial volume, oxidative DNA damage, and necrotic core areas in atherosclerotic plaques. In mice lacking VCAM-1 in macrophages, atherosclerosis and inflammation are less severe, and reduced expression of LYZ1 and FCOR, involved in STING signaling, is observed. Human carotid plaque macrophages also show a correlation between VCAM-1 expression and mitochondrial and DNA damage. The study highlights the role of macrophage VCAM-1 in inflammation and atherogenesis, proposing a self-acerbating pathway involving increased mtDNA synthesis. Cellular metabolism regulates macrophage function and atherosclerosis, with mtDNA synthesis playing a critical role in disease progression. Mitochondrial homeostasis is maintained by biogenesis and mitophagy, and mtDNA synthesis is regulated by genes such as PGC1A, CMPK2, and POLG. Aberrant mtDNA synthesis is linked to various diseases, including neurodegeneration and cancer. The study demonstrates that VCAM-1 enhances mtDNA synthesis in macrophages, leading to increased inflammation and atherosclerosis. VCAM-1 is expressed in macrophages in atherosclerotic plaques and is correlated with mitochondrial volume and oxidative DNA damage. The study also shows that VCAM-1 deficiency reduces mtDNA synthesis and inflammation, and that mtDNA synthesis genes such as CMPK2 and POLG are involved in regulating VCAM-1 downstream genes. The findings suggest that macrophage VCAM-1 exacerbates atherosclerosis by suppressing FCOR and LYZ1, which are involved in STING signaling. The study underscores the importance of targeting mtDNA synthesis in atherosclerosis.Mitochondrial DNA (mtDNA) synthesis in macrophages is linked to inflammation and atherosclerosis. This study shows that vascular cell adhesion molecule 1 (VCAM-1) in atherosclerotic plaque macrophages promotes mtDNA synthesis, which activates the STING pathway and exacerbates inflammation and atherosclerosis. VCAM-1 activates C/EBPα, which enhances the expression of key mitochondrial biogenesis genes, leading to increased mtDNA synthesis. This process is associated with higher mitochondrial volume, oxidative DNA damage, and necrotic core areas in atherosclerotic plaques. In mice lacking VCAM-1 in macrophages, atherosclerosis and inflammation are less severe, and reduced expression of LYZ1 and FCOR, involved in STING signaling, is observed. Human carotid plaque macrophages also show a correlation between VCAM-1 expression and mitochondrial and DNA damage. The study highlights the role of macrophage VCAM-1 in inflammation and atherogenesis, proposing a self-acerbating pathway involving increased mtDNA synthesis. Cellular metabolism regulates macrophage function and atherosclerosis, with mtDNA synthesis playing a critical role in disease progression. Mitochondrial homeostasis is maintained by biogenesis and mitophagy, and mtDNA synthesis is regulated by genes such as PGC1A, CMPK2, and POLG. Aberrant mtDNA synthesis is linked to various diseases, including neurodegeneration and cancer. The study demonstrates that VCAM-1 enhances mtDNA synthesis in macrophages, leading to increased inflammation and atherosclerosis. VCAM-1 is expressed in macrophages in atherosclerotic plaques and is correlated with mitochondrial volume and oxidative DNA damage. The study also shows that VCAM-1 deficiency reduces mtDNA synthesis and inflammation, and that mtDNA synthesis genes such as CMPK2 and POLG are involved in regulating VCAM-1 downstream genes. The findings suggest that macrophage VCAM-1 exacerbates atherosclerosis by suppressing FCOR and LYZ1, which are involved in STING signaling. The study underscores the importance of targeting mtDNA synthesis in atherosclerosis.