Ye Qing, Tang Yong
International Joint Research Centre On Purinergic Signalling, School of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
Purinergic Signal. 2025 May 5. doi: 10.1007/s11302-025-10090-x.
In a recent article published in Nature, 2025 Zhang et al. identified the pyrimidinergic receptor P2Y (P2YR), together with the cysteinyl leukotriene receptor 2 (CYSLTR2), as key receptor mediating ceramide-induced atherosclerotic cardiovascular disease (ASCVD). High levels of plasma ceramides bind to P2YR and CYSLTR2, activating the Gαq signaling pathway, which triggers NLRP3 inflammasome activation and the release of the pro-inflammatory cytokine IL-1β, thereby accelerating the progression of atherosclerosis. These findings provide credible evidence supporting the long-chain ceramides as clinical predictors for risks of ASCVD. Designing small-molecule drugs and antagonists that target the binding sites of ceramide-CYSLTR2/P2YR complexes presents a potential clinical strategy beyond traditional lipid-lowering therapies.
在最近发表于《自然》杂志的一篇文章中，张等人于2025年确定嘧啶能受体P2Y（P2YR）与半胱氨酰白三烯受体2（CYSLTR2）是介导神经酰胺诱导的动脉粥样硬化性心血管疾病（ASCVD）的关键受体。高水平的血浆神经酰胺与P2YR和CYSLTR2结合，激活Gαq信号通路，触发NLRP3炎性小体激活并释放促炎细胞因子IL-1β，从而加速动脉粥样硬化的进展。这些发现提供了可靠证据，支持长链神经酰胺作为ASCVD风险的临床预测指标。设计靶向神经酰胺-CYSLTR2/P2YR复合物结合位点的小分子药物和拮抗剂，是一种超越传统降脂疗法的潜在临床策略。
