动脉粥样硬化 z-bio 2025-03-28 296

　　Figure Ceramide accelerates atherosclerosis progression through CYSLTR2 and P2RY6 receptors

　　Under the support of the National Natural Science Foundation of China (Grant No.: 81921001, 82230010, 82270352, 82425105, 82330118), Professor Kong Wei and Jiang Changtao of Peking University, together with Professor Sun Jinpeng of Peking University/Shandong University and Professor Zheng Jingang of China-Japan Friendship Hospital, have made progress in the research on the pathogenesis of atherosclerosis regulated by Shenjingamide receptors. The research achievement is entitled "Sensing atherosclerosis by CYSLTR2 and P2RY6 to accelerate atherosclerosis", and will be published online in Nature on March 6, 2025. Paper link: https://www.nature.com/articles/s41586-025-08792-8#citeas .

　　Atherosclerosis is the main cause of cardiovascular disease. At present, lipid lowering therapy is mainly used, but there is still a significant residual risk of cardiovascular events that has not been resolved. Circulatory ceramide, as an independent risk factor of atherosclerotic cardiovascular disease, has gradually attracted attention, but its mechanism in disease progression is still unclear.

　　The research team found that cysteine leukotriene receptor 2 (CYSLTR2) and pyrimidine receptor P2Y6 (P2RY6) are endogenous receptors for ceramides. The research team successfully resolved the three-dimensional structure of the "ceramide C16:0-CYSLTR2-Gq" complex, revealing a specific binding pocket that determines the recognition of ceramide subtypes by CYSLTR2. Ceramide binds to these receptors and activates the downstream Gq protein mediated inflammatory body pathway, which plays a key role in the pathogenesis of atherosclerosis. Further animal experiments have confirmed that blocking the CYSLTR2 or P2RY6 ceramide receptors through gene knockout or specific antagonists can reduce plaque burden without affecting blood lipid levels, and the combined blocking effect of the two receptors is more significant. In addition, the clinical cohort study showed that the plasma ceramide level in patients with chronic kidney disease and coronary heart disease was significantly positively correlated with the degree of coronary artery disease, suggesting that ceramide may become a new biomarker of atherosclerotic cardiovascular disease (Fig.).

　　The results of this study reveal the structure and molecular mechanism of ceramide's initiation of transmembrane Gq and inflammatory body signal transduction through direct binding to CYSLTR2 and P2RY6 receptors. Blocking these signal transduction may provide a new treatment idea for atherosclerosis related diseases, and provide a theoretical basis for developing new treatment strategies.