Thioredoxin/thioredoxin reductase system (Trx/TrxR system)

The Thioredoxin/thioredoxin reductase system is a ubiquitous and essential cellular enzyme system composed primarily of thioredoxin (Trx), a small redox-active protein, and thioredoxin reductase (TrxR), a selenocysteine-containing flavoenzyme. Together, these proteins maintain the cellular redox environment by catalyzing electron transfer from NADPH (via TrxR) to protein disulfide bonds (via Trx), controlling redox signaling, antioxidative defense, and many fundamental processes such as DNA synthesis and repair, apoptosis, immune response, and metabolic regulation[1][2][3][5]. The system is evolutionary conserved and exists in several isoforms in mammals (TrxR1, TrxR2, TrxR3), with distinct subcellular localizations. Aberrant regulation or overexpression of components of this system is implicated in the pathogenesis of cancer, inflammatory disorders, cardiovascular diseases, neurodegeneration, and infection[1][5]. Multiple clinically or preclinically relevant compounds target this system to induce oxidative stress, especially in cancer cells, by inhibiting TrxR activity. However, due to its systemic importance, inhibition also risks toxicity in normal tissues[1][5].

Other names

Thioredoxin systemThioredoxin reductase (TrxR) and Thioredoxin (Trx)Trx systemNADPH-dependent thioredoxin system

Irreversible or competitive inhibition of thioredoxin reductase, causing disruption of redox homeostasis and leading to increased intracellular oxidative stress and apoptosis (e.g. by auranofin, arsenic trioxide)[1]. Targeting the active site selenocysteine of TrxR, leading to enzyme inactivation. Blockade of electron transfer from NADPH to thioredoxin, resulting in oxidation of cellular proteins and stress-induced cell death.