Mechanistically, celastrol could reduce the phosphorylation and nuclear translocation of STAT3 by targeting and inhibiting TLR4, thereby reducing the activation of NLRP3 inflammasomes and preventing macrophage pyroptosis.<h4>Conclusion</h4>The present study demonstrates for the first time that celastrol prevents macrophage pyroptosis by inhibiting TLR4/STAT3/NLRP3 signaling pathway, ultimately alleviating atherosclerosis. Here, STAT3 is linked to atherosclerosis.