CYSLTR2和P2RY6感知神经酰胺加重动脉粥样硬化，这一成果由北京大学孔炜课题组经过不懈努力而取得。2025年3月6日，国际知名学术期刊《自然》发表了这一成果。

课题组研究人员研究了循环长链神经酰胺是否激活膜G蛋白偶联受体（GPCR）以加剧动脉粥样硬化。该课题组人员结合G蛋白信号定量、GPCR表达的生物信息学分析和NLRP3炎性小体激活的功能检测进行了系统筛选，结果表明CYSLTR2和P2RY6是内皮细胞和巨噬细胞中C16:0神经酰胺诱发炎性小体激活的潜在内源性受体。该研究团队发现抑制CYSLTR2/P2RY6基因或药理学可减轻神经酰胺诱导的动脉粥样硬化加重。此外，神经酰胺水平升高与不同程度肾功能损害患者冠状动脉疾病的严重程度相关。

值得注意的是，CYSLTR2/P2RY6缺乏减轻了小鼠慢性肾脏疾病（CKD）加重的动脉粥样硬化，而不影响胆固醇或神经酰胺水平。神经酰胺-CYSLTR2-Gq复合物的结构分析表明，C16:0和C20:0神经酰胺结合在CYSLTR2上的倾斜通道状配体结合口袋内。课题组研究人员进一步揭示了神经酰胺诱导CYSLTR2活化和CYSLTR2-Gq界面的非常规机制。总的来说，他们的研究提供了长链神经酰胺通过直接结合CYSLTR2和P2RY6受体启动跨膜Gq和炎性体信号传导的结构和分子机制，阻断这些信号传导可能为治疗动脉粥样硬化相关疾病提供新的治疗潜力。

据悉，最近的证据表明，循环长链神经酰胺水平升高可独立于胆固醇预测动脉粥样硬化性心血管疾病（ASCVD）。尽管靶向神经酰胺信号传导可能提供治疗高胆固醇血症以外的益处，但循环神经酰胺加重ASCVD的潜在机制仍不清楚。

附：英文原文

Title: Sensing ceramides by CYSLTR2 and P2RY6 to aggravate atherosclerosis

Author: Zhang, Siting, Lin, Hui, Wang, Jiale, Rui, Jingyu, Wang, Tengwei, Cai, Zeyu, Huang, Shenming, Gao, Yanxiang, Ma, Tianfeng, Fan, Rui, Dai, Rongbo, Li, Zhiqing, Jia, Yiting, Chen, Qiang, He, HaoMing, Tan, Jiaai, Zhu, Shirong, Gu, Rui, Dong, Zhigang, Li, Meihong, Xie, Enmin, Fu, Yi, Zheng, Jingang, Jiang, Changtao, Sun, Jinpeng, Kong, Wei

Issue&Volume: 2025-03-06

Abstract: Recent evidence shows elevated circulating long-chain ceramide levels predict atherosclerotic cardiovascular disease (ASCVD) independently of cholesterol1,2. Although targeting ceramide signaling may provide therapeutic benefits beyond the treatment of hypercholesterolemia, the underlying mechanism by which circulating ceramides aggravate ASCVD remains elusive. We examined whether circulating long-chain ceramides activate membrane G protein-coupled receptors (GPCRs) to exacerbate atherosclerosis. We performed a systematic screen combining G protein signaling quantification, bioinformatic analysis of GPCRs expression, and functional examination of NLRP3 inflammasome activation, and the results suggested CYSLTR2 and P2RY6 are potential endogenous receptors of C16:0 ceramide-evoked inflammasome activation in both endothelial cells and macrophages. We found that inhibiting CYSLTR2/P2RY6 genetically or pharmacologically alleviated ceramide-induced atherosclerosis aggravation. Additionally, increased ceramide levels correlated with the severity of coronary artery disease in patients with varying degrees of renal impairment. Notably, CYSLTR2/P2RY6 deficiency mitigated chronic kidney disease (CKD)-aggravated atherosclerosis in mice, without affecting cholesterol or ceramide levels. Structural analysis of the ceramide-CYSLTR2-Gq complexes revealed that both C16:0 and C20:0 ceramides bind within an inclined channel-like ligand binding pocket on CYSLTR2. We further revealed an unconventional mechanism underlying ceramides-induced CYSLTR2 activation and CYSLTR2-Gq interface. Overall, our study provided structural and molecular mechanisms that long-chain ceramides initiate transmembrane Gq and inflammasome signaling through directly binding to CYSLTR2 and P2RY6 receptors, and blocking these signaling may provide new therapeutic potential to treat atherosclerosis-related diseases.

DOI: 10.1038/s41586-025-08792-8

Source: https://www.nature.com/articles/s41586-025-08792-8