Thioredoxin reductase (TrxR) (TrxR)

Thioredoxin reductase (TrxR) is a family of selenium-containing flavoenzymes essential for maintaining cellular redox homeostasis by reducing oxidized thioredoxin (Trx) using NADPH as an electron donor [1, 6]. In mammals, three main isoforms exist: the cytosolic TXNRD1, the mitochondrial TXNRD2, and the testis-specific TXNRD3 [1, 13]. Beyond its primary role in antioxidant defense, the TrxR system supports critical processes such as DNA synthesis via ribonucleotide reductase, protein repair, and the regulation of transcription factors like NF-κB and p53 [6, 7]. TrxR is frequently overexpressed in various cancers, where it promotes tumor cell survival, proliferation, and resistance to therapy by neutralizing excessive reactive oxygen species (ROS) [8, 14]. Consequently, it has emerged as a prominent therapeutic target, with drugs like auranofin and ethaselen designed to inhibit its activity, thereby inducing oxidative stress-mediated apoptosis in malignant cells [2, 5]. However, the high reactivity of its selenocysteine active site poses challenges for selectivity, as inhibition can also affect normal cellular functions and other selenoproteins [7, 14].

Other names

TXNRDThioredoxin-disulfide reductaseTRSelenoprotein TXNRD1Thioredoxin reductase 1Thioredoxin reductase 2Thioredoxin reductase 3

Thioredoxin reductase inhibitors primarily function by covalently binding to the highly reactive C-terminal selenocysteine residue of the enzyme [3, 8]. This modification irreversibly inactivates the enzyme, preventing the reduction of oxidized thioredoxin and other substrates [1, 2]. The resulting depletion of reduced thioredoxin leads to an accumulation of reactive oxygen species (ROS), disruption of redox-sensitive signaling pathways, and the induction of apoptosis, particularly in cancer cells which are highly dependent on the thioredoxin system for survival under oxidative stress [5, 7].