ADHFE1 (alcohol dehydrogenase iron containing 1) is a mitochondrial enzyme that catalyzes the cofactor-independent reversible oxidation of gamma-hydroxybutyrate (GHB) to succinic semialdehyde coupled to reduction of 2-ketoglutarate to D-2-hydroxyglutarate (D-2-HG) 1. The enzyme represents the first characterized iron-activated alcohol dehydrogenase in humans, showing homology to microbial iron-activated alcohol dehydrogenases rather than other human alcohol dehydrogenases 2. ADHFE1 plays critical roles in development and cellular differentiation, regulating Hox gene expression during embryonic trunk patterning by modulating retinoic acid levels through retinaldehyde reduction 3. In colorectal cancer, ADHFE1 functions as a differentiation marker, with normal expression highest in mature crypt epithelium and downregulation associated with cancer progression through promoter hypermethylation 4. Conversely, ADHFE1 acts as an oncogene in breast cancer, where MYC upregulates its expression, leading to D-2-HG accumulation and metabolic reprogramming that promotes tumor growth 1. ADHFE1 methylation status serves as a biomarker for colorectal cancer screening 5 and gastric cardia cancer diagnosis 6. The dual role of ADHFE1 as both tumor suppressor and oncogene highlights its tissue-specific functions in cancer development and progression.