ACER3 is an endoplasmic reticulum and Golgi-localized alkaline ceramidase that catalyzes hydrolysis of unsaturated long-chain ceramides (C18:1, C20:1, C20:4) into sphingosine and free fatty acids at alkaline pH 1. The enzyme functions as a zinc-dependent amidase with conserved catalytic residues forming its active site 1. ACER3 regulates sphingoid base generation, particularly controlling sphingosine-1-phosphate levels in plasma and erythrocytes, which mediate cell proliferation, apoptosis, and differentiation signaling 2. In hepatocellular carcinoma, ACER3 promotes cell growth via S1P/S1PR2/PI3K/AKT signaling; ACER3 knockdown decreases proliferation and increases apoptosis 2. ACER3 expression is dysregulated in multiple diseases: elevated in cholestatic liver injury where ACER3 ablation attenuates hepatic necrosis and inflammation 3; upregulated during liver ischemia/reperfusion injury where it increases oxidative stress via respiratory complex I activation 4; and associated with poor glioma prognosis through LINC01087/miR-1277-5p regulatory networks 5. In asthma, ACER3 acts as a hub lipid metabolism gene inversely correlating with CD8+ T cell and NK cell infiltration 6. Dysregulation of ACER3 expression and ceramide metabolism contributes to inflammatory and neoplastic diseases, suggesting therapeutic potential for ACER3 targeting.