CERS2 encodes ceramide synthase 2, an endoplasmic reticulum enzyme that catalyzes the synthesis of ceramides by transferring acyl chains from acyl-CoA to sphingoid bases, with high selectivity for very-long-chain fatty acyl-CoA substrates (C22–C27). The enzyme plays non-redundant roles in synthesizing ceramides with very-long-chain fatty acids in kidney, liver, and brain, where it regulates myelin-specific sphingolipids that affect myelin architecture and motor neuron function. CERS2 activity is tightly integrated with immune and metabolic homeostasis. Loss of IL-10 signaling drives accumulation of saturated very-long-chain ceramides through CERS2, promoting aberrant inflammatory gene expression dependent on the transcription factor REL 1. Similarly, dysregulation of CERS2-dependent ceramide production impairs adipose tissue function and glucose homeostasis; blocking de novo ceramide biosynthesis rescues these defects 2. In pancreatic β-cells, CERS2 ablation selectively reduces insulin content and impairs glucose tolerance, with effects mediated through altered sphingolipid–protein interactions affecting proinsulin processing 3. Clinically, CERS2 variants associate with progression from gestational diabetes to type 2 diabetes in Hispanic women, with loss-of-function alleles impairing β-cell function and glucose homeostasis 4. A CERS2 polymorphism (rs267734) correlates with accelerated albuminuria progression in diabetic patients 5. Very-long-chain ceramides mediated by CERS2 also drive endothelial dysfunction in aortic aneurysm 6 and contribute to 1-deoxysphingolipid toxicity in neuropathy 7. These findings identify CERS2 as a convergence point for metabolic and inflammatory disease pathogenesis.