The main findings of this study included (1) UBA1 expression was upregulated and mainly derived from macrophages in the diet-induced atherosclerotic plaques, (2) inhibition of UBA1 did not alter main metabolic parameters after atherogenic diet feeding, and (3) inhibition of UBA1 decreased atherosclerosis development by reducing macrophage inflammatory responses and oxidative stress. This evidence concerns the gene UBA1 and atherosclerosis.