ACER2 (alkaline ceramidase 2) is a Golgi-localized membrane enzyme that catalyzes ceramide hydrolysis into sphingosine and free fatty acids at alkaline pH, with preference for unsaturated long-chain ceramides 1. The enzyme requires Ca2+ for activity and possesses seven transmembrane domains with its N-terminal tail essential for proper Golgi localization and function 1. ACER2 regulates sphingolipid homeostasis by controlling sphingosine-1-phosphate (S1P) and dihydrosphingosine-1-phosphate production, bioactive lipids governing cell proliferation, apoptosis, and autophagy 2. The enzyme participates in p53-dependent DNA damage responses and modulates protein glycosylation through sphingosine production 1. Clinically, ACER2 dysregulation contributes to multiple diseases. In diabetic retinopathy, elevated ACER2 expression provides negative feedback to reduce ceramide accumulation and endothelial dysfunction 3. Conversely, in diffuse large B-cell lymphoma, YTHDF2-mediated stabilization of ACER2 mRNA promotes ceramide catabolism, activating pro-survival AKT/PI3K pathways 4. In prostate cancer bone metastasis, miR-140-3p suppression of ACER2 inhibits autophagy via AKT/mTOR activation, promoting progression 5. UMP administration alleviates obesity by restoring HIF2α-ACER2-mediated ceramide catabolism 6. ACER2 represents a critical metabolic node in gastrointestinal cancers through S1P pathway regulation 2.