P2Y₆R together with CYSLTR2 serves as endogenous receptor for long-chain ceramides in atherosclerosis

In a recent article published in Nature, 2025 Zhang et al. identified the pyrimidinergic receptor P2Y₆ (P2Y₆R), 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 P2Y₆R 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/P2Y₆R complexes presents a potential clinical strategy beyond traditional lipid-lowering therapies.