Crucial role of AKR1B in immune cell function and its implications on inflammatory conditions

What is it about?

This article provides an overview of studies related to Aldo-keto reductase 1B (AKR1B) focusing on how AKR1B regulates immune cell function, particularly in macrophages and T cells. It also delves into the impact of dysregulated AKR1B on various immunometabolism-related diseases such as gastrointestinal diseases, psoriasis, inborn disorders of glycosylation, and cancers. The article summarizes a decade of target development efforts by leading pharmaceutical companies against this enzyme family, highlighting the challenges and limitations that have hindered clinical progress. Initially recognized as key enzymes in the polyol pathway, a branch of glucose metabolism, the AKR1B subfamily was primarily implicated in the development of chronic complications of diabetes such as retinopathy, neuropathy, nephropathy, and cataracts. However, more recent research has shown that AKR1B is not only involved in the reduction of aldehydes, steroids, and their by-products but also in the conversion of lipid peroxidation products. Furthermore, AKR1B plays a crucial role in reshaping the metabolism of immune cells and generating signaling molecules. The polyol pathway is activated in immune cells under high glucose conditions or during inflammation, leading to the conversion of glucose and galactose to sorbitol and galactitol by AKR1B/Akr1b. Accumulation of sugar alcohols such as sorbitol can disrupt the metabolism of other organic metabolites such as fructose, taurine, and inositol, potentially contributing to the development of cardiovascular, neurodegenerative, and metabolic diseases. The intricate metabolic network of immune cells underscores the importance of regulating AKR1B/Akr1b expression, which can affect macrophage and T-cell function, thereby influencing immune responses and disease progression. A better understanding of the mechanisms that control AKR1B/Akr1b expression in immune cells may provide new insights and targets for the treatment of various AKR1B/Akr1b-related immunometabolism disorders, including gastrointestinal diseases, psoriasis, congenital disorders of glycosylation, and cancer.

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Photo by julien Tromeur on Unsplash

Photo by julien Tromeur on Unsplash

Why is it important?

The significance of AKR1B as a potential pharmaceutical target is evident due to the importance of its three isoenzymes. Although several inhibitors have been developed, their translation into drugs for diabetic complications has been challenging. AKR1B's role in reducing toxic aldehydes under conditions of oxidative stress adds complexity to the specificity of enzyme inhibition. Investigation of the functional properties of AKR1B and its inhibitors is essential to refine inhibition specificity. Challenges in the development of AKR1B inhibitors include the potential impact on other physiological processes due to the enzyme's widespread presence of the enzyme in the human body, the need for clinical validation of efficacy and safety, and bioavailability issues. Overcoming these obstacles will require focused research efforts to formulate safer, more efficient, and easily applicable AKR1B inhibitors. Despite the current complexities, understanding the involvement of AKR1B in immune cell function and inflammatory conditions can guide the exploration of novel therapeutic approaches. Advances in structural biology and computational drug design utilizing AI techniques present hopeful opportunities for further advancement and application of AKR1B inhibitors in clinical environments.

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