Abstract
In a recent article published in Nature, 2025 Zhang et al. identified the pyrimidinergic receptor P2Y(6) (P2Y(6)R), 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 P2Y(6)R 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/P2Y(6)R complexes presents a potential clinical strategy beyond traditional lipid-lowering therapies.