AKR1B15 (aldo-keto reductase family 1 member B15) is a mitochondrial enzyme that exhibits unique substrate specificity and subcellular localization compared to other AKR family members. Alternative splicing produces two isoforms: AKR1B15.1 (316 amino acids) localizes to mitochondria and is catalytically active, while AKR1B15.2 (344 amino acids) is cytosolic and enzymatically inactive 1. AKR1B15.1 functions primarily as a reductive enzyme with strong cofactor selectivity toward NADP(H), catalyzing the reduction of androgens and estrogens with 17β-hydroxysteroid dehydrogenase activity, as well as reducing 3-keto-acyl-CoA conjugates 1. The enzyme shows superior catalytic efficiency with 9-cis-retinaldehyde compared to all-trans-retinaldehyde, distinguishing it from the closely related AKR1B10 2. AKR1B15 is highly expressed in steroid-sensitive tissues including placenta, testis, and adipose tissue 1, and shows elevated expression in the upper regions of the human intestine 3. The enzyme's unique substrate specificity and inhibitor selectivity result from a smaller, more hydrophobic active site containing key phenylalanine residues 24. Clinical relevance includes potential roles in hepatocellular carcinoma prognosis 5 and pathological keratinization of ocular surfaces 6.