Gentisic acid prevents the development of atherosclerotic lesions by inhibiting SNX10-mediated stabilization of LRP6

Atherosclerotic-related acute cardiovascular events remain a leading cause of mortality worldwide, yet there are currently no pharmacological interventions available to address plaque formation or plaque rupture (PR). Here we reported that gentisic acid (GA) exerted potent therapeutic effects on plaque formation and PR in a dose-dependent manner by inhibiting LRP6-mediated macrophage apoptosis. By using the CETSA assay and DARTS assay, we identified sorting nexin 10 (SNX10) as the direct target of GA. The binding of GA to SNX10 disrupts the interaction between SNX10 and LRP6, leading to the degradation of LRP6. The downregulation of LRP6 then significantly attenuated the activation of Wnt/β-catenin pathway to exert an inhibitory effect on apoptosis. Moreover, the specific depletion of SNX10 in macrophages significantly reduced LRP6 levels and subsequently macrophage apoptosis both in vivo and in vitro. In conclusion, our findings not only suggest that GA may serve as a potential therapeutic candidate for the prevention of atherosclerosis and acute cardiovascular events caused by PR, but also confirm the druggability of SNX10 as a promising therapeutic target for atherosclerotic rupture. • GA alleviates the development of atherosclerotic plaques via inhibiting LRP6/Wnt/β-catenin-mediated apoptosis. • SNX10 is identified as the direct target of GA. • GA impedes the binding of LRP6 to SNX10, leading to the degradation of LRP6. • SNX10 is a potential target for atherosclerotic-related disease.