CERS4 (ceramide synthase 4) catalyzes de novo ceramide synthesis by converting sphinganine and long/very-long chain acyl-CoA substrates (C18:0-C22:0) into ceramides, primarily generating C18-C20 species 1. Located in the endoplasmic reticulum, CERS4 functions as a sphingolipid N-acyltransferase with roles extending beyond lipid metabolism into cellular signaling and immune regulation. Metabolically, CERS4 represents a key control point in obesity-related dysfunction. Intestinal MYC transcriptionally upregulates CERS4 in obese individuals; reducing CERS4 expression improves high-fat-diet-induced obesity, insulin resistance, and hepatic steatosis by promoting GLP-1 production 2. In liver, CERS4 forms complexes with ELOVL6 and PNPLA3 to regulate hepatic ceramide(d18:1/18:0) composition and insulin signaling 3. Clinically, CERS4 dysregulation drives cancer pathogenesis and immunotherapy responses. CERS4 overexpression in breast cancer activates oncogenic pathways (NF-κB, Akt/mTOR, Wnt/β-catenin) and promotes chemoresistance through ABC transporter upregulation and EMT 1. In triple-negative breast cancer, CERS4-altered ceramide metabolism triggers PD-L1 internalization and immunotherapy resistance 4. Conversely, high CERS4 expression predicts favorable anti-PD-1 responses in NSCLC via CERS4/Rhob/Tim-3 axis modulation 5. In colorectal cancer, CERS4 downregulation associates with KRAS mutations and increased vascular invasion 6. Additionally, CERS4 maintains hair follicle stem cell identity and skin barrier integrity through sphingolipid-dependent Wnt signaling control 7.