ACER1 is an endoplasmic reticulum ceramidase that catalyzes the hydrolysis of ceramides into sphingosine and free fatty acids at alkaline pH. This enzyme exhibits substrate specificity toward natural ceramides, particularly those with very long-chain unsaturated fatty acids such as C24:1-ceramide. Ceramides, sphingosine, and sphingosine-1-phosphate are bioactive lipids regulating cell proliferation, apoptosis, and differentiation. ACER1 is predominantly a skin-specific enzyme that plays a critical role in epidermal homeostasis. It mediates calcium-induced differentiation of keratinocytes and maintains appropriate ceramide levels in the epidermis. ACER1-deficient mice exhibit elevated skin ceramides, cyclic alopecia, sebaceous gland dysfunction, and increased transepidermal water loss, demonstrating its essential role in skin barrier function and whole-body energy homeostasis 1. Beyond skin, recent evidence reveals broader inflammatory roles for ACER1. In platelets, ACER1-mediated ceramide catabolism suppresses pro-inflammatory cytokine secretion and platelet-leukocyte aggregation, reducing abdominal aortic aneurysm susceptibility in mice 2. In the intestine, ACER1 inhibition attenuates colitis in mice with impaired manganese homeostasis 3. In head and neck squamous cell carcinoma, ACER1 downregulation correlates with poor prognosis and reduced immune infiltration, suggesting tumor-suppressive functions 4. ACER1 downregulation also occurs in atopic dermatitis lesions, where its restoration alongside targeted therapeutics like tapinarof and tofacitinib improves epidermal barrier function 5.