CERS5 (ceramide synthase 5) is a key enzyme catalyzing ceramide biosynthesis by transferring acyl chains from palmitoyl-CoA (C16:0-CoA) to sphingoid bases, with high selectivity for C16 chain length 1. CERS5 localizes to the endoplasmic reticulum and participates in both de novo and salvage pathway ceramide synthesis 1, generating the abundant d18:1,16:0 ceramide species that functions as a signaling lipid 2. CERS5 regulates distinct biological processes through its specific sphingolipid products. In metabolic disease, PAQR4-mediated stabilization of CERS5 increases ceramide levels, impairing adipose tissue function and glucose homeostasis; blocking CERS5-catalyzed ceramide synthesis rescues these defects 3. Notably, CerS5 and CerS6 produce distinct C16 sphingolipid pools with different signaling consequences—only CerS6-derived ceramides interact with the mitochondrial fission factor Mff 4. In cancer, CERS5 promotes hepatocellular carcinoma progression through lipophagy and represents a therapeutic target 5. CERS5 expression affects gastric cancer proliferation, migration, and invasion 6, and alternative splicing of CERS5 regulates glioma malignancy 7. In cardiovascular disease, CerS5 deletion reduces aortic valve stenosis development, inflammation, and calcification in high-fat diet conditions 2. Additionally, estrogen upregulates CERS5 expression via AP-1 activation in breast cancer cells 8.