Aldo-keto reductases (AKRs) are a superfamily of NAD(P)(H)-dependent oxidoreductases, catalyzing the reduction of carbonyl groups to corresponding alcohols [1]. The details about this family can also be found on the website -https://akrsuperfamily.org/. Aldehydes are converted to primary alcohols and ketones are converted to secondary alcohols by AKRs [2]. The AKR superfamily contains 16 families; in mammals three enzyme families exist and are AKR1, AKR6, and AKR7 [3]. AKR1 is one of the largest families in the AKR superfamily and is composed of six subfamilies (https://www.med.upenn.edu/akr/) [4].The enzymes in this family carry out a wide range of biological and pathological functions, including carbonyl detoxification, osmolytic regulation and hormonal metabolism [5] AKR7A, which falls within the AKR7 subfamily, is the closest to AKR1 rather than AKR6 which contains the human β-subunits of the voltage-dependent potassium channel [5].

Rat AKR7A1 was first identified AKR7A member in 1993 [6]. To date, five AKR7A members from three species have been identified including rat AKR7A1 and AKR7A4, human AKR7A2 and AKR7A3, and mouse AKR7A5, and several structures, substrate specificities and biological functions were also determined as summarized in Fig. 1 [[7], [8], [9], [10], [11]]. Rat AKR7A1 and human AKR7A3 exhibit 80 % sequence identity [11], AKR7A2 and 7A3 shares 88 % sequence identity. AKR7A4 has only 79 % sequence identity to AKR7A1, but has high sequence identity of 87 % to AKR7A5 (Fig. 2) [12]. AKR7A enzymes catalyze a range of aldehydes and ketones to alcohols with NADPH as a cofactor, leading to their bioactivation or detoxification (Fig. 3) [8,[13], [14], [15]]. AKR7A members serve as potent protective effectors against chemical-induced hepatotoxicity [2,14,[16], [17], [18], [19], [20]]. The expression levels of AKR7As are associated with many diseases including hepatocellular carcinoma (HCC), breast cancer, gastric cancer and neurodegenerative diseases (Fig. 4) [2,16,[21], [22], [23], [24]], suggesting that these enzymes are potential disease biomarkers and drug targets [2,[21], [22], [23], [24], [25]]. Transcriptional factor Nrf2 (nuclear factor erythroid 2 p45-related factor 2) controls the expression of multiple AKR7As including AKR7A1, AKR7A2 and AKR7A3, which is also responsible for the high inducibility of AKR7A in the presence of antioxidants [[26], [27], [28]].

This review will summarize and update the biology of AKR7A members in substrate specificity, organ distribution, crystal structure, gene expression and biological functions, and the involvement of AKR7As in the metabolism of drugs, carcinogens, and reactive aldehydes.