Beyond cholesterol: targeting ceramide signaling in cardiorenal metabolic crosstalk

Cardiovascular-Kidney-Metabolic (CKM) syndrome is associated with increased risks of cardiovascular mortality and target organ failure. Despite optimal lipid-lowering therapies, patients remain at substantial residual risk for adverse cardio-renal outcomes. Conventional cholesterol-centric models do not fully account for this inter-organ pathology, limiting precision risk assessment and intervention. Emerging evidence suggests that ceramides, key intermediates in sphingolipid metabolism, may function as circulating signaling molecules involved in inter-organ communication. Recent studies have identified several putative ceramide-responsive receptors through which ceramides may contribute to lipotoxic injury in remote organs. They have been associated with pathological processes including insulin resistance, renal microvascular injury, and atherosclerosis, particularly in the context of impaired renal function. Based on a systematic literature search, this review summarizes the cross-organ pathogenic mechanisms of ceramides in CKM syndrome. We evaluate the role of ceramide-based risk scores (e.g., CERT1) in risk stratification and critically discuss the opportunities and challenges associated with emerging therapeutic strategies.