ADH5 (alcohol dehydrogenase 5) is a zinc-containing enzyme primarily responsible for metabolizing long-chain primary alcohols and omega-hydroxy fatty acids, including 20-HETE, through NAD+-dependent oxidation 1. Notably, ADH5 is remarkably ineffective at oxidizing ethanol, distinguishing it from other alcohol dehydrogenases. A critical housekeeping function of ADH5 is formaldehyde detoxification; the enzyme catalyzes oxidation of this cytotoxic and carcinogenic metabolite to prevent DNA damage accumulation 2. ADH5 also functions as S-nitrosoglutathione reductase (GSNOR), regulating protein S-nitrosylation through NADH-dependent reduction of S-nitrosoglutathione 3. Mechanistically, ADH5 operates in conjunction with ALDH2 as a dual aldehyde clearance system essential for preventing lethal formaldehyde accumulation 4. Deficiency in formaldehyde clearance—either through ADH5 or ALDH2 loss—results in profound hematopoietic dysfunction, including hematopoietic stem cell depletion and formaldehyde-DNA adduct accumulation 4. ADH5 dysfunction also accelerates hematopoietic stem cell aging through p53-mediated responses to formaldehyde-induced genotoxic stress 5. Disease associations include bone marrow failure syndromes and AMED syndrome 4. Clinically, ADH5 represents a therapeutic target for conditions involving aldehyde toxicity, including alcoholic liver disease and hematological malignancies 6.