Glutathione and Thioredoxin antioxidant systems (GSH/Trx systems)

The Glutathione (GSH) and Thioredoxin (Trx) systems are the two primary independent yet cross-talking antioxidant pathways responsible for maintaining cellular redox homeostasis (Harris et al., 2015, Nature). In cancer cells, elevated metabolic activity and oncogenic signaling result in high levels of reactive oxygen species (ROS), making these cells uniquely dependent on these antioxidant systems to prevent oxidative damage and cell death (Gorrini et al., 2013, Nature Reviews Drug Discovery). The GSH system relies on enzymes like glutathione peroxidase and reductase, while the Trx system centers on thioredoxin and thioredoxin reductase (TXNRD) (Lu and Holmgren, 2014, Free Radical Biology and Medicine). Therapeutic strategies often involve inhibiting these systems—using agents like auranofin for TrxR or buthionine sulfoximine for GSH synthesis—to push cancer cells past their antioxidant threshold into apoptosis or ferroptosis (Koppula et al., 2018, Nature Reviews Cancer). Because these systems can compensate for one another, dual inhibition is frequently explored to overcome resistance and enhance efficacy in high-ROS tumors (Zhang et al., 2017, Cancer Cell). Targeting these pathways is particularly effective in inducing ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation (Stockwell et al., 2017, Cell). However, the challenge remains in achieving selectivity for cancer cells over normal cells that also require redox maintenance.

Other names

GSH and Trx antioxidant pathwaysCellular redox homeostasis systemsThiol-dependent antioxidant systemsGSH-Trx redox network

Inhibition of key enzymes and transporters within the glutathione and thioredoxin pathways to disrupt redox homeostasis, leading to lethal accumulation of reactive oxygen species and induction of oxidative stress-mediated cell death, such as apoptosis or ferroptosis.