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Chronic stress (CS) is recognized as a contributing factor to the progression of atherosclerosis (AS), but the molecular mechanisms within the central nervous system (CNS) remain poorly understood. In this study, we established mouse models for CS and AS, including normal control (CON), AS, CS, and AS + CS groups, and analyzed gene expression in brain tissues. We identified Cxcr4 and Gng4 as key genes differentially expressed in response to AS and CS. Elevated expression of CXCR4 and GNG4 in the frontal cortex was observed in the CS and AS + CS groups compared to the CON and AS groups. CS not only induced neuronal damage but also exacerbated AS progression, as evidenced by larger atherosclerotic plaque areas in the AS + CS group, increased abdominal aorta intima‒media thickness (IMT), and reduced abdominal aorta lumen diameter (AUD) in the CS and AS + CS groups. The upregulation of Cxcr4 and Gng4 in brain tissue correlated positively with IMT and negatively with AUD, and their combined expression demonstrated strong predictive potential for IMT and AUD. Furthermore, Cxcr4 and Gng4 mRNA levels were significantly positively correlated. Additionally, CXCR4 and GNG4 colocalized, interacted, and formed stable complexes, both of which were detectable in neurons. Moreover, CS upregulated circulating levels of CXCL12, CXCR4, GNG4, and pro-inflammatory cytokines (IL-6, IL-1β). These findings suggest that CS-induced upregulation of CXCR4 and GNG4 in brain tissue and serum may amplify inflammatory responses and contribute to the progression of AS, highlighting potential therapeutic targets for stress-related cardiovascular diseases. KEY MESSAGES: • Chronic stress induced neuronal damage, exacerbated circulating inflammatory responses and AS progression. • Cxcr4 and Gng4 were identified as hub genes associated with both chronic stress and atherosclerosis, chronic stress increased the expression of CXCR4 and GNG4 in the brain tissue and serum. • The upregulation of Cxcr4 and Gng4 in brain tissue correlated positively with abdominal aorta intima‒media thickness (IMT) and negatively with abdominal aorta lumen diameter (AUD), and their combined expression demonstrated strong predictive potential for IMT and AUD. • Cxcr4 and Gng4 mRNA levels were significantly positively correlated, CXCR4 and GNG4 colocalized, interacted, and formed stable complexes, both of which were detectable in neurons.