CerS6, short for ceramide synthase 6, is a key enzyme in sphingolipid metabolism. It is involved in synthesizing specific ceramide species, such as C16-0 sphingolipids, which play crucial roles in various biological pathways. Sphingolipids are bio-reactive molecules that transmit signals and are associated with processes like mitochondrial dynamics, cell migration, and immune responses. Genetic models, including knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in studying CerS6's functions [1,2,3,4,5].

In obesity, CerS6-derived sphingolipids bind to the mitochondrial fission factor (Mff), promoting mitochondrial fragmentation. Ablation of CerS6 protects from obesity and insulin resistance, revealing its role in the link between hepatic lipid deposition and mitochondrial fragmentation [1].

In diabetic kidney disease, CerS6-derived ceramides inhibit PINK1-mediated mitophagy by potentially binding to the PINK1 protein, exacerbating renal interstitial fibrosis. Cers6 deficiency reduces abnormal ceramide accumulation, restores mitophagy, and attenuates fibrosis [2].

In ulcerative colitis, FTO deficiency downregulates CerS6, leading to S1P accumulation in intestinal epithelial cells, which triggers pro-inflammatory macrophage responses and Th17 cell differentiation, aggravating colitis [3].

In hypothalamic neurons of obese mice, CerS6-dependent ceramide synthesis promotes ER/mitochondrial stress and impairs glucose homeostasis. Conditional deletion of CerS6 in specific hypothalamic neurons alleviates high-fat diet-induced weight gain and improves glucose metabolism [4].

In diabetic kidney disease, podocyte-specific CerS6 knockout ameliorates glomerular injury and inflammatory responses, while overexpression induces proteinuria. CerS6-derived ceramide binds to VDAC1, initiating mtDNA leakage and promoting an immune-inflammatory response [5].

In lung cancer, CERS6 overexpression is associated with poor prognosis and lymph node metastasis. Reducing CERS6 expression decreases cell migration and invasion activities, and CERS6 knockdown suppresses lung metastasis in mice [6].

In conclusion, CerS6 is essential in sphingolipid-mediated biological processes. KO and CKO mouse models have revealed its significant roles in obesity, diabetes-related kidney diseases, ulcerative colitis, glucose homeostasis regulation, and cancer metastasis. Understanding CerS6's functions through these models provides potential therapeutic targets for metabolic diseases, kidney diseases, and cancer [1,2,3,4,5,6].