Samd8, also known as Sphingomyelin synthase-related protein (SMSr), is an endoplasmic reticulum-resident ceramide phosphoethanolamine (CPE) synthase. It plays a crucial role in sphingolipid biosynthesis, monitoring endoplasmic reticulum ceramide levels to prevent inappropriate cell death. The N-terminal sterile α-motif (SAM) domain of the enzyme is also important for its function [4,5,6,7].

In non-alcoholic fatty liver disease (NAFLD) studies, Smsr KO mice showed attenuated high-fat diet/fructose-induced fatty liver, NASH, and glucosylceramide accumulation-induced NASH, fibrosis, and tumor formation. SMSr/PE-PLC deficiency reduced the expression of many inflammatory cytokines and fibrosis-related factors [3]. In the context of glioma, SAMD8 was identified as a prognostic factor within a m5C-related module, and a signature including SAMD8 was significant in predicting patient survival [1]. In diabetic nephropathy, SAMD8 was identified as a lipid metabolism-related gene that may play a key role, with its high expression confirmed in DN samples [2].

In conclusion, Samd8 is essential for maintaining ceramide homeostasis during sphingolipid biosynthesis and preventing apoptosis. Through gene knockout models, its role in diseases such as NAFLD, glioma, and diabetic nephropathy has been revealed. These findings contribute to understanding the biological functions of Samd8 and provide potential targets for the treatment of related diseases.