TXNIP: A key protein in the cellular stress response pathway and a potential therapeutic target

Abstract

Thioredoxin-interacting protein (TXNIP), which is also known as thioredoxin-binding protein 2 (TBP2), directly interacts with the major antioxidant protein thioredoxin (TRX) and inhibits its antioxidant function and expression. However, recent studies have demonstrated that TXNIP is a multifunctional protein with functions beyond increasing intracellular oxidative stress. TXNIP activates endoplasmic reticulum (ER) stress-mediated nucleotide-binding oligomerization domain (NOD)-like receptor protein-3 (NLRP3) inflammasome complex formation, triggers mitochondrial stress-induced apoptosis, and stimulates inflammatory cell death (pyroptosis). These newly discovered functions of TXNIP highlight its role in disease development, especially in response to several cellular stress factors. In this review, we provide an overview of the multiple functions of TXNIP in pathological conditions and summarize its involvement in various diseases, such as diabetes, chronic kidney disease, and neurodegenerative diseases. We also discuss the potential of TXNIP as a therapeutic target and TXNIP inhibitors as novel therapeutic drugs for treating these diseases.

Metabolism: A protein target for diverse disorders

A protein with the potential to fuel uncontrolled inflammation and cell death could offer a target for a variety of metabolic, neurodegenerative, and other diseases. The cellular redox system is a set of reactions that helps prevent accumulation of toxic byproducts of metabolism. Stressful conditions lead to the activation of the TXNIP protein, an inhibitor of the redox system, and Eui-Hwan Choi and Sun-Ji Park at the Daegu-Gyeongbuk Medical Innovation Foundation, South Korea, have reviewed how TXNIP contributes to diverse pathophysiological states. For example, TXNIP-mediated redox inhibition is associated with the nervous system inflammation seen in Alzheimer’s disease, and also contributes to premature death of insulin-secreting cells in patients with diabetes. Several drugs have been identified that can reduce TXNIP activity, and ongoing preclinical studies are now examining the therapeutic potential of such agents.