Ceramide: A critical lipid mediator in the progression of diabetic nephropathy

Diabetic nephropathy (DN) is one of the most severe microvascular complications of diabetes mellitus (DM). The complex pathogenesis is driven by the synergistic effects of glycotoxicity and lipotoxicity. In recent years, ceramides, especially C16:0 ceramides as the core hub of sphingolipid metabolism, have been shown to participate in the development of DN. This systematic review examines the mechanisms of ceramides metabolic dysregulation in DN, elucidating the molecular triggers responsible for selective accumulation of C16:0 ceramides under hyperglycemia and insulin-resistant conditions. Central to this analysis is the role of C16:0 ceramides in orchestrating interconnected pathological signaling pathways-endoplasmic reticulum stress (ERS), mitochondrial dysfunction, NLRP3 inflammasome activation, exosome-mediated inflammatory amplification, autophagy impairment, and cytoskeletal disorganization-which collectively are linked to renal cell injury, proteinuria, and renal fibrosis. Notably, the emerging role of podocyte-derived exosomes as carriers of inflammasome products recruiting immune cells and amplifying glomerular inflammation is highlighted.From a clinical perspective, the translational potential of plasma ceramide profiling (particularly C16:0/C24:0 ratio) and urinary exosome-based liquid biopsy as biomarkers for early diagnosis is explored. Furthermore, emerging therapeutic strategies targeting ceramide metabolism and exosome release are summarized, with emphasis on the potential of combining ceramide-targeted interventions with current renal triple therapy. This review provides a comprehensive framework linking ceramide-mediated lipotoxicity to DN progression and outlines future directions for precision prevention and treatment.