Abstract
Thioredoxin-interacting protein (TXNIP), widely known as thioredoxin-binding protein 2 (TBP2), is a major binding mediator in the thioredoxin (TXN) antioxidant system, which involves a reduction-oxidation (redox) signaling complex and is pivotal for the pathophysiology of some diseases. TXNIP increases reactive oxygen species production and oxidative stress and thereby contributes to apoptosis. Recent studies indicate an evolving role of TXNIP in the pathogenesis of complex diseases such as metabolic disorders, neurological disorders, and inflammatory illnesses. In addition, TXNIP has gained significant attention due to its wide range of functions in energy metabolism, insulin sensitivity, improved insulin secretion, and also in the regulation of glucose and tumor suppressor activities in various cancers. This review aims to highlight the roles of TXNIP in the field of diabetology, neurodegenerative diseases, and inflammation. TXNIP is found to be a promising novel therapeutic target in the current review, not only in the aforementioned diseases but also in prolonged microvascular and macrovascular diseases. Therefore, TXNIP inhibitors hold promise for preventing the growing incidence of complications in relevant diseases.
Highlights
Thioredoxin-interacting protein (TXNIP) was first identified in cancer cells as a vitaminD3 target gene and later known as vitamin D3 upregulated protein 1 (VDUP1)
TXNIP, activates the NLRP3 inflammasome and caspase 1 to stimulate the release and maturation of interleukin 1β (IL-1β) and IL-18. Further elucidation of this phenomenon suggests maintenance of the macrophage and β-cell activation in an autocrine and paracrine manner, thereby intensifying the inflammatory responses [30]. Pyroptosis is another type of programmed cell death associated with inflammatory caspase 1 and proinflammatory regulators that are common in necrosis and apoptosis [27], and is closely linked to the activation of the inflammatory pathway
Direct transcription control is evident in HepG3 cells, where the loss of TXNIP is associated with significantly elevated expression of glucose transporter 1 (Glut1) and high uptake of glucose
Summary
Thioredoxin-interacting protein (TXNIP) was first identified in cancer cells as a vitamin. TXNIP further modulates TXN’s protein structure while reorganizing de novo disulfide bond synthesis on Cys, with unique residues at positions 32 and 247, respectively [2,3] Several antioxidants, such as thioredoxin, glutaredoxin, and glutathione, help to maintain the activity of the TXN-system via a cell-based redox (reduction/oxidation) mechanism, which could face direct oxidative stress if ROS production is dysregulated [4]. TXNIP has emerged as an essential metabolic regulator of lipid and glucose metabolism [22] It modulates the transcription of several genes, each of which points to new mechanisms implicating TXNIP as a therapeutic target in several disorders [23,24,25,26]. This review is aimed at highlighting the roles of TXNIP in the field of diabetology, neurodegenerative diseases, and inflammation
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