Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook

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.

Keywords: TXNIP; TXNIP modulator; metabolic disorders; neurological disorders; thioredoxin.

Figure 1

Upstream mediators of TXNIP signaling. Possible signaling mechanisms by which TXNIP launches abnormal signaling resulting in disease symptoms may include the following. In glucose metabolism, the elevation in glucose uptake correlates with an increase in mRNA expression of Glut1, which is supported by TXNIP regulation; the blue line indicates the modulation of glucose metabolism via inhibition of its breakdown and uptake; TLR4 action mediated by MyD88 activates the NF-κB pathway, where it interacts with the main intermediaries of inflammation in a TXNIP/NLRP3-associated manner and alleviates pyroptosis; upregulated oxidative stress and multiple upstream intermediaries upregulate ROS, which further elevates TXNIP expression, thereby disrupting the interaction of TXN and ASK1. Hence, liberated ASK1 upon interaction with caspase 3 leads to generic apoptosis; the ERS-mediated TXNIP-associated inflammasome pathway drives apoptosis and inflammation with an eventual release of cytokines (IL-1β and IL-18). Inflammatory-pathway upstream inducers include ROS, glucose, and ERS. ERS: endoplasmic-reticulum stress; PERK: protein kinase RNA-like ER kinase; IRE1α: inositol-requiring enzyme 1α; eIF-2α: eukaryotic translation initiation factor 2α; TLR4: toll-like receptor 4; TXN: thioredoxin; TXNR: thioredoxin reductase; TXNIP: thioredoxin-interacting protein; NLRP3 inflammasome: Nod-like receptor protein 3 inflammasome; IL-1β: interleukin 1β; ATF5: activating transcription factor 5; ChREBP: carbohydrate response element–binding protein; ROS: reactive oxygen species; ASK1: apoptosis signal-regulating kinase; Overexpression(↑); Inhibition(⊣); Involving intermediaries (⇢).

Figure 2

The role of TXNIP in the development of various diseases. Elevated TXNIP expression may lead to the development of various diseases while contributing to these pathologies via distinct mechanisms. NAFLD: non-alcoholic fatty liver disease; ROS: reactive oxygen species; TXNIP: thioredoxin-interacting protein; Upregulation (↑); Downregulation (↓).