Macrophage P2Y6 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 P2Y₆ 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 P2Y₆ receptors contribute to foam cell formation and plaque development through the phospholipase Cβ (PLCβ)/store-operated Ca²⁺ entry/calreticulin/scavenger receptor A (SR-A) pathway. Furthermore, the study identifies thiamine pyrophosphate (TPP) as a potent P2Y₆ receptor antagonist, effectively inhibiting foam cell formation and reducing plaque burden in atherosclerotic mice, without inducing toxicity. These findings establish P2Y₆ receptors as promising therapeutic targets in atherosclerosis and introduce TPP as a potential clinical candidate for intervention.