ACER1 (alkaline ceramidase 1) is an endoplasmic reticulum membrane enzyme that catalyzes the hydrolysis of ceramides into sphingosine and free fatty acids at alkaline pH 1. The enzyme exhibits strong substrate specificity for natural D-erythro-sphingosine-containing ceramides, with higher activity toward very long-chain unsaturated fatty acids like C24:1-ceramide 1. ACER1 functions as a skin-specific ceramidase that regulates sphingolipid homeostasis in the epidermis and mediates calcium-induced keratinocyte differentiation 1. Loss of ACER1 function leads to elevated ceramide levels in skin, aberrant hair formation, cyclic alopecia, increased transepidermal water loss, and hypermetabolism with reduced fat content 2. Beyond skin biology, ACER1 plays protective roles in vascular inflammation, where platelet-specific ACER1 deficiency increases susceptibility to abdominal aortic aneurysm formation through ceramide-p38 MAPK signaling 3. In inflammatory bowel disease, ACER1 maintains epithelial integrity, and ACER1 inhibition can attenuate colitis by remedying barrier dysfunction 4. Additionally, ACER1 functions as a tumor suppressor in head and neck squamous cell carcinoma, with reduced expression correlating with poor prognosis and altered immune infiltration 5.