CERS3 (ceramide synthase 3) is an endoplasmic reticulum-localized enzyme that catalyzes the synthesis of ceramides with very-long and ultra-long-chain fatty acids (>C22) 1. The enzyme transfers acyl chains from acyl-CoA to sphingoid bases, producing dihydroceramides and ceramides through both de novo synthesis and salvage pathways 1. CERS3 is crucial for epidermal lipid homeostasis and barrier function, specifically synthesizing acylceramides essential for stratum corneum formation 1. The enzyme's activity is regulated by acyl-CoA-binding protein (ACBP), which can increase CERS3 activity up to 7-fold by facilitating very-long-chain acyl-CoA substrate availability 2. CERS3 expression is modulated by inflammatory cytokines, with Th1/Th17 cytokines upregulating its expression in keratinocytes 3. Disease relevance includes autosomal recessive congenital ichthyosis type 9, where CERS3 mutations severely reduce acylceramide levels in the stratum corneum despite preserved protein-bound ceramide levels 1. Additionally, CERS3 plays roles in cancer progression, with elevated activity contributing to colorectal cancer through increased C26 ceramide production 4. Therapeutic targeting of CERS3 represents a promising approach for treating both skin barrier disorders and certain cancers.