Emerging role of ceramides and other sphingolipids in atherosclerosis

Atherosclerotic cardiovascular disease (ASCVD) remains the foremost cause of mortality worldwide. Despite the proven efficacy of statins and other low-density lipoprotein cholesterol (LDL-C) lowering therapies, a significant residual cardiovascular risk persists, highlighting the need to identify pathogenic pathways beyond traditional cholesterol management. Emerging evidence identifies sphingolipids-bioactive lipids structurally based on a sphingoid backbone-as critical modulators of vascular homeostasis and the progression of atherosclerosis. This review examines the complex biosynthetic and metabolic networks governing sphingolipid metabolism, with a specific focus on the "sphingolipid rheostat", a dynamic signaling axis determined by the balance between the pro-apoptotic and pro-inflammatory effects of ceramides; and the anti-inflammatory and pro-survival effects of sphingosine-1-phosphate (S1P). We discuss the multifaceted role of ceramide accumulation in driving LDL aggregation, endothelial dysfunction, foam cell formation, and vascular smooth muscle cell (VSMC) phenotype alteration and function. Conversely, we highlight the protective functions of S1P, particularly its role in maintaining endothelial barrier integrity and modulating inflammatory responses via high-density lipoprotein (HDL)-associated chaperones. We further discuss how complex sphingolipids-such as sphingomyelin and glycosphingolipids-influence lesion initiation and progression. By elucidating the interplay between these lipid mediators and the vascular and immune cells in the atheroma, this review highlights the sphingolipid metabolic network as a promising source of therapeutic interventions to target residual atherosclerotic risk beyond LDL lowering.