CERS2 (ceramide synthase 2) catalyzes the synthesis of ceramides with very-long-chain fatty acids (C22-C27) by transferring acyl-CoA groups to sphingoid bases, forming both dihydroceramides and ceramides in de novo and salvage pathways 12. The enzyme plays a non-redundant role in kidney, liver, and brain tissues, regulating myelin-specific sphingolipids including galactosylceramide and sulfatide that are essential for myelin architecture and motor neuron function 3. Mechanistically, CERS2 activity directly influences systemic inflammatory and metabolic responses. IL-10 signaling suppresses saturated very-long-chain ceramide accumulation through altered fatty acid desaturation, preventing pathologic REL-dependent inflammation 4. PAQR4 regulates CERS2 protein stability; elevated CERS2 activity causes ceramide accumulation that impairs adipogenesis and glucose homeostasis 5. In pancreatic β-cells, CERS2-derived very-long-chain sphingolipids control proinsulin processing and insulin secretion through interactions with endoplasmic reticulum-Golgi transport proteins like Tmed2 6. Clinically, CERS2 dysfunction associates with multiple metabolic diseases: reduced CERS2 activity impairs glucose homeostasis and β-cell function in gestational diabetes-to-type 2 diabetes progression 7; decreased ovarian CERS2 expression correlates with nervonic acid accumulation and impaired reproductive function in metabolic syndrome 8; CERS2 inhibition protects hematopoietic stem cells against endoplasmic reticulum stress and radiation injury 9; and CERS2 drives toxic very-long-chain dihydroceramide formation in hereditary sensory neuropathy and diabetic neuropathy 10.