2. Academic Validation
  3. Gentisic acid prevents the development of atherosclerotic lesions by inhibiting SNX10-mediated stabilization of LRP6

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

  • Pharmacol Res. 2024 Dec:210:107516. doi: 10.1016/j.phrs.2024.107516.
Tongqing Chen 1,  Yiming Wang 2,  Jia-Lin Yang 3,  Jiahui Ni 1,  Keyuan You 1,  Xuesong Li 3,  Yuping Song 3,  Xu Wang 1,  Jian Li 4,  Xiaoyan Shen 5,  Yujuan Fan 6,  Yan You 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
  • 2 Department of Cardiology, Worldwide Medical Center, Huashan Hospital, Fudan University, Shanghai, China.
  • 3 Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, China.
  • 4 Department of Cardiology, Worldwide Medical Center, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: 13816066763@163.com.
  • 5 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China; Innovative Center for New Drug Development of Immune Inflammatory Diseases, Ministry of Education, Shanghai, China. Electronic address: shxiaoy@fudan.edu.cn.
  • 6 Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, China. Electronic address: fanyujuan22@sohu.com.
  • 7 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China; Innovative Center for New Drug Development of Immune Inflammatory Diseases, Ministry of Education, Shanghai, China. Electronic address: yyou@fudan.edu.cn.
PMID: 39603572 DOI: 10.1016/j.phrs.2024.107516
Abstract

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.

Keywords

Apoptosis; Gentisic acid; LRP6; Plaque rupture.

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