A groundbreaking study led by Professor Kong Wei of Peking University and Professor Sun Jinpeng of Shandong University, published in Nature on March 7, reveals CYSLTR2 and P2RY6 as endogenous receptors for ceramide C16:0, a lipid molecule directly linked to atherosclerotic plaque formation. This discovery identifies a novel mechanism by which ceramides exacerbate vascular inflammation and accelerate cardiovascular disease progression.

The research demonstrates that ceramide C16:0 activates Gq proteins through CYSLTR2 and P2RY6, triggering inflammasome activation and promoting plaque development. In animal models, these receptors' genetic deletion or pharmacological inhibition significantly reduced atherosclerosis without affecting lipid levels. Dual receptor blockade showed synergistic therapeutic effects, suggesting a promising strategy for clinical intervention.

Notably, structural analysis of the "C16:0-CYSLTR2-Gq" complex unveiled an unconventional binding mode, providing critical insights for future drug design. The study further validated ceramide levels as independent biomarkers for coronary lesion severity in chronic kidney disease (CKD) patients, highlighting their role in CKD-associated cardiovascular risk.

Background and Clinical Implications

Atherosclerosis, driven by lipid plaque accumulation in blood vessels, remains a leading cause of heart attacks and strokes. Despite statins reducing LDL cholesterol and lowering adverse event risks by ~30%, residual cardiovascular risks persist, particularly in CKD patients. Ceramides, termed the "second cholesterol," have long been associated with cardiovascular risk, but their mechanistic role in atherosclerosis was previously unclear.

This work reshapes the understanding of residual lipid risk and opens avenues for precision therapies. "Targeting ceramide receptors could complement existing treatments, especially for high-risk populations like CKD patients," the researchers emphasized. The findings advance the field by bridging mechanistic insights with translational potential, offering new biomarkers and therapeutic targets to address unmet clinical needs.