Aerobic exercise plays an important role in prevention and treatment of atherosclerosis. Inflammatory response is the main pathological process during occurrence and development stage of atherosclerosis. SESNs are considered as anti-inflammation protein in atherosclerosis. In current study, a high expression level of SESN1 is identified under the condition of aerobic exercise, further investigation shows levels of IL-1β/IL-6/TNF-α are significantly suppressed compared to those atherosclerosis mice with no aerobic training. Besides, we find that the activation of NF-κB signaling is impeded. Combine with our previous study, SESN1 is considered as the downstream factor of aerobic exercise which tend to inhibit the activation of inflammatory signaling and results in suppressing the expression level of inflammatory factors. Another exciting finding is that MMP9/13 are also suppressed，but the potential mechanism is unclear. Overall, present study sheds light on the significance of aerobic exercise for inflammation and stability of plaque through SESN1 may help developing new clinical treatments of atherosclerosis.Copyright © 2021 Elsevier Inc. All rights reserved.