Macrophage P2Y receptor signalling as a key mediator and therapeutic target in atherosclerosis.

Atherosclerosis, a chronic inflammatory disease driven by lipid deposition and immune cell activation, remains a leading cause of cardiovascular morbidity and mortality. Emerging evidence highlights the role of purinergic signalling in atherogenesis, particularly the P2Y receptor in macrophages [1]. Using RNA sequencing, proteomics, expression and functional validation in cells, mouse models and human materials, this study provides comprehensive mechanistic insights into how macrophage P2Y receptors contribute to foam cell formation and plaque development through the phospholipase Cβ (PLCβ)/store-operated Ca entry/calreticulin/scavenger receptor A (SR-A) pathway. Furthermore, the study identifies thiamine pyrophosphate (TPP) as a potent P2Y receptor antagonist, effectively inhibiting foam cell formation and reducing plaque burden in atherosclerotic mice, without inducing toxicity. These findings establish P2Y receptors as promising therapeutic targets in atherosclerosis and introduce TPP as a potential clinical candidate for intervention.