TRIM21 Promotes Endothelial Cell Activation via Accelerating SOCS3 Ubiquitination Degradation in Atherosclerosis

Activated endothelial cells play an important role in the beginning of atherosclerotic disease by secreting various proteins and inflammatory cytokines. Ubiquitination is one of the most common post-translational changes in cells. However, the role and mechanisms of ubiquitination in endothelial cell activation remain poorly understood. In this study, we identified TRIM21 as an E3 ubiquitin ligase with increased expression in atherosclerotic disease and activated endothelial cells. Knockdown of TRIM21 resulted in reduced secretion of inflammatory factors and attenuated the pyroptosis of endothelial cells, inhibiting the progression of atherosclerosis. Mechanistically, TRIM21 could bind and ubiquitinate SOCS3, thereby enhancing NLRP3-mediated pyroptosis. Taken together, we found that endothelial TRIM21 activated the JAK/STAT3 pathway by degrading SOCS3, which in turn promoted NLRP3-mediated pyroptosis and aggravated atherosclerosis, revealing that TRIM21 may be a promising treatment target for the medical management of atherosclerosis.