Aldo-keto reductases (AKRs) are a group of NAD(P)(H)-dependent enzymes catalyzing interconversions between the carbonyl and alcohol groups of endogenous and xenobiotic compounds [
1]. The AKR superfamily is systematized into 16 families: AKR1 (aldehyde reductases, aldose reductases, hydroxysteroid dehydrogenases, and steroid 5b-reductases); AKR2 (mannose and xylose reductases); AKR3 (yeast AKRs); AKR4 (chalcone and codeinone reductases); AKR5 (gluconic acid reductases); AKR6 (β-subunits of the potassiumgated voltage channels); AKR7 (aflatoxin dialdehyde and succinic semialdehyde reductases); AKR8 (pyridoxal reductases); AKR9 (aryl alcohol dehydrogenases); AKR10 (
Streptomyces AKRs); AKR11 (
Bacillus AKRs); AKR12 (
Streptomyces sugar aldehyde reductases); AKR13 (hyperthermophilic bacteria reductases); AKR14 (
Escherichia coli reductases), AKR15 (
Mycobacterium reductases), and AKR16 (
Vibrio cholerae reductases). Each family is further divided into several subfamilies based on a >60% amino acid sequence identity. To date, fifteen AKR members have been identified in humans and belong to the AKR1A, AKR1B, AKR1C, AKR1E, AKR6A, and AKR7A subfamilies. There are three members of the human AKR1B subfamily: AKR1B1 (aldose reductase), AKR1B10 (aldose reductase-like protein-1), and AKR1B15, whose genes are clustered at chromosome 7q33 [
1]. AKR1B1, AKR1B10, and an enzymatically active isoform of AKR1B15 are 36-kDa soluble monomeric proteins consisting of 316 amino acids and sharing >68% amino acid sequence identity, of which 91.5% are shared between AKR1B10 and AKR1B15 [
2,
3]. The three AKRs are NADPH-dependent reductases and display overlapping substrate specificities for aromatic and aliphatic aldehydes but differ in their catalytic efficiencies [
2,
3,
4,
5,
6], which is notably higher for retinal (all-
trans-retinaldehyde) in AKR1B10 [
5]. In addition, the glucose reductase activity characteristics of AKR1B1 are very low for AKR1B10 and AKR1B15 [
2,
4,
5], and prostaglandin F synthase activity is observed with AKR1B1, but not with AKR1B10 [
7]. In contrast to AKR1B1, AKR1B10 and AKR1B15 exhibit low 17β-hydroxysteroid dehydrogenase activity for estrone and 4-androstene-3,17-dione [
3,
6]. For subcellular localization, AKR1B1 and AKR1B10 are cytosolic, whereas AKR1B15 is in the mitochondria [
3]. The three AKR1Bs also have different tissue distributions. While AKR1B1 is ubiquitous, AKR1B10 protein is predominantly expressed in the human stomach and intestine [
2,
8], although its mRNA is detected in many other tissues [
3,
8,
9]. The mRNA for AKR1B15 is predominantly expressed in the placenta, testis, skeletal muscle, and adipose tissue, where its level is lower than that of mRNA for AKR1B10 [
3].
While the most studied enzyme of the AKR1B subfamily is AKR1B1, which has been implicated in the pathogenesis of diabetes complications and inflammatory disease [
10,
11], many studies of AKR1B10 have focused on its association with cancers and other diseases since its overexpression in hepatocellular carcinomas (HCC) was found in 1998 [
12]. In addition to its role in gastrointestinal homeostasis, increasing evidence suggests that the aberrant expression of AKR1B10 promotes its diagnostic and prognostic utility as a potential tumor biomarker and elucidates its role in carcinogenesis, tumor progression, and the development of chemoresistance. In this review, we summarize recent progress towards understanding the gene regulation of AKR1B10 and its functions in gastrointestinal physiology, the pathogenesis of several cancers and skin diseases, and acquired drug resistance. Based on the available evidence, we propose that AKR1B10 is thus a potential target for drug discovery. We also provide a brief overview of AKR1B10 inhibitors.