CERS5 is a ceramide synthase that catalyzes the transfer of palmitoyl-CoA (C16:0-CoA) to sphingoid bases, producing C16-ceramides through both de novo and salvage sphingolipid pathways. The enzyme localizes to the endoplasmic reticulum membrane and shows high selectivity for C16 acyl donors, with acyl-CoA specificity determined by a 150-residue region within its TLC domain 1. In cancer contexts, CERS5 plays context-dependent roles. In hepatocellular carcinoma, CERS5 promotes tumor progression through lipophagy, and inhibiting CERS5 alongside LPCAT1 represents a potential therapeutic strategy 2. In gastric cancer, CERS5 knockdown reduces proliferation and migration while increasing apoptosis 3. Conversely, in advanced colorectal cancer, reduced CERS5 expression enhances tumor formation and correlates with worse survival in late-stage patients, suggesting CERS5 expression level may guide personalized treatment decisions 4. In glioma, CERS5 alternative splicing regulates sphingolipid metabolism and represents a therapeutic vulnerability 5. Beyond oncology, CERS5 influences metabolic and cardiovascular disease. Loss of CERS5 protects from aortic valve stenosis development in mice on a Western diet by reducing inflammation and calcification 6, and PAQR4-mediated regulation of CERS5 controls ceramide homeostasis in adipose tissue, affecting glucose metabolism 7.