It is reported that oxidative stress homeostasis was involved in PM 2.5 -induced foam cell formation and progression of atherosclerosis, but the exact molecular mechanism is still unclear. Melatonin is an effective antioxidant that could reverse the cardiopulmonary injury. The main purpose of this study is to investigate the latent mechanism of PM 2.5 -triggered atherosclerosis development and the protective role of melatonin administration. Vascular Doppler ultrasound showed that PM 2.5 exposure reduced aortic elasticity in ApoE-/- mice. Meanwhile, blood biochemical and pathological analysis demonstrated that PM 2.5 exposure caused dyslipidemia, elicited oxidative damage of aorta and was accompanied by an increase in atherosclerotic plaque area; while the melatonin administration could effectively alleviate PM 2.5 -induced macrophage M1 polarization and atherosclerosis in mice. Further investigation verified that NADPH oxidase 2 (NOX2) and mitochondria are two prominent sources of PM 2.5 -induced ROS production in vascular macrophages. Whereas, the combined use of two ROS-specific inhibitors and adopted with melatonin markedly rescued PM 2.5 -triggered macrophage M1 polarization and foam cell formation by inhibiting NOX2-mediated crosstalk of Keap1/Nrf2/NF-κB and TLR4/TRAF6/NF-κB signaling pathways. Our results demonstrated that NOX2-mediated oxidative stress homeostasis is critical for PM 2.5 -induced atherosclerosis and melatonin might be a potential treatment for air pollution-related cardiovascular diseases. [Display omitted] • PM 2.5 exposure triggers macrophage M1 polarization and foam cell formation. • NOX2-mediated crosstalk of Keap1 and TLR4 pathway is critical for PM 2.5 -induced atherosclerosis. • Melatonin can alleviate PM 2.5 -triggered atherosclerosis via oxidative stress homeostasis. [ABSTRACT FROM AUTHOR]