Figure 2: TXNIP binds to Trx and inhibits its anti-oxidant and thiol reducing function. The Trx-TrxR-NADPH axis is critical for cellular redox balance. However, under TXNIP overexpression in diabetes, TXNIP binds to Trx via disulfide bond formation between Trx (Cys 32) and TXNIP (Cys 247) and inactivates Trx activity [177-178]. (A) Initially, a mild ROS stress generated by TXNIP-Trx interaction may induce second phage anti-oxidant genes and chaperones such as superoxide dismutases SOD1 and SOD2, catalase and heme oxygenase (HO-1) and heat shock proteins (e.g., hsp70, hsp60, hsp40, and hsp27). (B) However, prolonged TXNIP overexpression and excessive ROS stress cause Trx thiol oxidation and cellular ROS/RNS stress leading to programmed cell apoptosis or necroptosis. In addition, release of TXNIP from oxidized Trx1 initiates NLRP3 inflammasome assembly (containing ASC), caspase-1 activation and processing of pro-IL-1b to mature IL-1b. Currently, whether TXNIP is or is not involved in inflammasome assembly is an area of intense research and whether cysteine residues in TXNIP form disulfide bond or S-nitrosylation under ROS/RNS stress is yet to be understood.