Aldo-keto reductases and role in human disease

Aldo-keto reductases (AKRs) are soluble NAD(P)(H) oxidoreductases that primarily catalyze the reduction of aldehydes and ketones to primary and secondary alcohols, respectively. The ten known human AKR enzymes can turnover a vast range of endogenous and exogenous substrates, including glucose, steroids, carcinogens, reactive aldehydes, and a variety of carbonyl-containing drugs. In recent years, the AKR enzymes have been implicated in a number of human diseases. As the rate limiting enzyme of the polyol pathway of glucose metabolism, AKR1B1 has long been known for its involvement in diabetic complications. Recent studies now suggest AKR1B1 play a key role in inflammatory diseases such as atherosclerosis, sepsis, asthma, uveitis, and colon cancer by mediating oxidative stress-induced inflammatory signals. AKRs are also implicated in the development and progression of many cancers as well as chemotherapeutic drug resistance. AKR1B1 and AKR1B10 were found to be overexpressed in tumors, such as liver, breast, and lung cancer. Several AKRs (AKR1A1, AKR1B10, and AKR1C1-3) are involved in tobacco-carcinogenesis because they activate polycyclic aromatic trans-dihydrodiols to yield reactive and redox active o-quinones, but they also catalyze the detoxication of nicotine derived nitrosamino ketones. In addition, AKR1C1-3 enzymes play a key role in the regulation of proliferative signaling in hormone dependent cancers. In recognition of the role of AKR in various diseases, significant efforts have been made in the development of specific/selective AKR1B1 and AKR1C3 inhibitors. The aim of this Research Topic forum is to celebrate the advancements seen in the AKR field via review papers and original articles as well as to promote future research in understanding the underlying mechanism(s) of the role of AKRs in human disease.