CerS6, or ceramide synthase 6, is a key enzyme in sphingolipid metabolism, responsible for synthesizing specific ceramide species, such as C16:0 sphingolipids. Sphingolipids are bio-reactive molecules involved in various cellular signaling pathways, and their metabolism is crucial for maintaining normal cell function. CerS6-related sphingolipid metabolism has been linked to multiple biological processes, including mitochondrial dynamics, mitophagy, and innate immune responses, which are all vital for normal physiological function and disease prevention [1-5].

In obesity, abrogation of CerS6 protects from obesity and insulin resistance as CerS6-derived C16:0 sphingolipids bind the mitochondrial fission factor (Mff), promoting mitochondrial fragmentation [1]. In diabetic kidney disease, Cers6 deficiency reduces abnormal ceramide accumulation, restores PTEN-induced kinase 1 (PINK1)-mediated mitophagy in renal tubular epithelial cells, and attenuates interstitial fibrosis [2]. Conditional deletion of CerS6 in hypothalamic neurons of obese mice alleviates weight gain and improves glucose metabolism [3]. Podocyte-specific CerS6 knockout ameliorates glomerular injury and inflammatory responses in male diabetic mice [4].

In conclusion, CerS6 plays essential roles in sphingolipid-mediated biological processes. Gene knockout and conditional knockout mouse models have revealed its significant contributions to obesity-related metabolic diseases, diabetic kidney disease, and other conditions. Understanding CerS6 function provides potential therapeutic targets for these diseases.

References:

1. Hammerschmidt, Philipp, Ostkotte, Daniela, Nolte, Hendrik, Brügger, Britta, Brüning, Jens C. . CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondrial Fragmentation in Obesity. In Cell, 177, 1536-1552.e23. doi:10.1016/j.cell.2019.05.008. https://pubmed.ncbi.nlm.nih.gov/31150623/

2. Wang, Xiangyu, Song, Minkai, Li, Xiaomin, Zhang, Chao, Xue, Yaoming. 2023. CERS6-derived ceramides aggravate kidney fibrosis by inhibiting PINK1-mediated mitophagy in diabetic kidney disease. In American journal of physiology. Cell physiology, 325, C538-C549. doi:10.1152/ajpcell.00144.2023. https://pubmed.ncbi.nlm.nih.gov/37458434/

3. Hammerschmidt, Philipp, Steculorum, Sophie M, Bandet, Cécile L, Brodesser, Susanne, Brüning, Jens C. 2023. CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice. In Nature communications, 14, 7824. doi:10.1038/s41467-023-42595-7. https://pubmed.ncbi.nlm.nih.gov/38016943/

4. Zhu, Zijing, Cao, Yun, Jian, Yonghong, Ding, Guohua, Chen, Zhaowei. 2025. CerS6 links ceramide metabolism to innate immune responses in diabetic kidney disease. In Nature communications, 16, 1528. doi:10.1038/s41467-025-56891-x. https://pubmed.ncbi.nlm.nih.gov/39934147/