CERS6 (ceramide synthase 6) catalyzes the transfer of palmitoyl-CoA (C16:0-CoA) to sphingoid bases, producing C16:0-ceramides in de novo and salvage sphingolipid pathways 1. This enzyme is localized to the endoplasmic reticulum and possesses high selectivity for C16:0 acyl donors, though it can utilize other substrates with reduced efficiency 2. Mechanistically, CERS6-derived C16:0-ceramides function as signaling lipids with multiple metabolic effects. They specifically bind mitochondrial fission factor (Mff), promoting mitochondrial fragmentation under high-fat diet conditions 3. Additionally, CERS6-ceramides can interact with mitochondrial VDAC1, triggering mtDNA leakage and activating cGAS-STING inflammatory signaling 4. CLINICAL SIGNIFICANCE: CERS6 upregulation associates with multiple metabolic diseases. In obesity, elevated CERS6 expression in adipose tissue correlates with insulin resistance, and CerS6 deletion protects from high-fat-diet-induced obesity and glucose intolerance 5. In diabetic kidney disease and focal segmental glomerulosclerosis, increased podocyte CERS6 correlates negatively with glomerular filtration rate and positively with proteinuria 4. CERS6 also contributes to ulcerative colitis progression through sphingolipid dysregulation 6 and alcohol-associated liver disease development 7. Notably, a fungal-derived CerS6 inhibitor ameliorates metabolic dysfunction-associated steatohepatitis 8, positioning CERS6 inhibition as a therapeutic target for metabolic and inflammatory diseases.