Abstract

Thoracic aortic dissection (TAD) is a life-threatening vascular pathology with limited therapeutic options. The role of the small molecule STF083010, a novel IRE1α RNase-specific inhibitor, in TAD has not yet been defined. We aimed to target the IRE1α-XBP1s axis pharmacologically using STF083010, and evaluate its therapeutic potential in the occurrence and progression of TAD. Using a β-aminopropionitrile monofumarate (BAPN)-induced murine TAD model combined with interleukin 1β (IL1β)-stimulated vascular smooth muscle cells (VSMCs), we systematically evaluated the effects of STF083010 on the development of TAD as well as VSMCs' phenotypic switching and vascular inflammation. Our study reveals that STF083010 administration significantly attenuates TAD formation in vivo. Furthermore, we identified STF083010 confers VSMCs with resistance to IL1β-induced VSMCs inflammation and phenotypic switching. Mechanistically, STF083010 restrains IRE1α-XBP1s axis and suppresses NLRP3 inflammasome activation-dependent pyroptosis, further inhibiting VSMCs phenotypic switching and inflammatory activation, and eventually alleviates the progress of TAD. Our findings establish STF083010 as a potential molecule drug for the prevention of TAD and provide mechanistic insights for developing innovative therapies in aortic pathologies. Graphical STF083010 is identified as a potential molecular drug for the prevention of TAD. STF083010 restrains the IRE1α-XBP1s axis and suppresses NLRP3 inflammasome activation-dependent pyroptosis, further conferring VSMCs with resistance to IL1β-induced phenotypic switching and inflammatory activation, eventually alleviating the progress of TAD.