Sphingolipids in human disease: organ-specific pathologies, chain-length-dependent effects, and translational implications

Sphingolipids, particularly ceramide (Cer) and sphingomyelin (SM), are critical for cellular homeostasis, serving as both essential membrane components and key signaling molecules. This review systematically classifies sphingolipid disorders by organ system, emphasizing chain-length-dependent effects such as the pro-inflammatory role of C16-Cer versus the protective functions of C24-Cer in disease. The review details sphingolipid involvement across seven major organ systems. In cardiovascular disease, SM(d18:1/16:1) contributes to atherosclerotic plaque instability, while Cer promotes NLRP3 inflammasome activation. In neurodegenerative diseases, an altered Cer/SM ratio disrupts lipid raft integrity and accelerates pathogenic protein aggregation. In oncology, cancer progression is facilitated through mechanisms like nSMase-mediated exosome release and CerS6-dependent metastasis. Translational applications are emerging, including Cer-based biomarkers with high diagnostic accuracy for early stroke and investigational aSMase inhibitors for atherosclerosis. Modulating sphingolipid metabolism presents a promising therapeutic strategy for precision medicine. However, challenges remain in deciphering tissue-specific regulatory networks and standardizing lipidomic methodologies.