Glutathione redox pathway (GSH pathway) (GSH pathway)

Glutathione (GSH) is a vital tripeptide (gamma-glutamyl-cysteinyl-glycine) that functions as the primary endogenous antioxidant in eukaryotic cells (PubChem CID 124886). The glutathione redox pathway consists of the enzymes and reactions responsible for the synthesis, recycling, and utilization of GSH to neutralize reactive oxygen species and detoxify electrophilic compounds (StatPearls: Glutathione). Key components include glutamate-cysteine ligase (GCL), glutathione synthetase (GSS), glutathione peroxidase (GPX), and glutathione reductase (GSR) (UniProt P36969, P14619). This system plays a pivotal role in maintaining cellular redox balance and protecting cells from oxidative damage, which is often exploited by cancer cells to resist therapy (PubMed: 23523445). Consequently, the pathway is a major focus in oncology for inducing ferroptosis—a form of iron-dependent regulated cell death—by inhibiting GPX4 or depleting GSH (PubMed: 29053968). Additionally, boosting the pathway's capacity is a therapeutic strategy for treating acetaminophen overdose and various neurodegenerative conditions characterized by oxidative stress (NIH: LiverTox). Drugs targeting this pathway range from GSH precursors like N-acetylcysteine to small molecule inhibitors like RSL3 that specifically target GPX4 (PubMed: 29053968).

Other names

Glutathione systemGSH metabolismGlutathione antioxidant systemGSH-GSSG cycleGlutathione and components of the glutathione redox pathway

Modulation of cellular glutathione levels through precursor supplementation or synthesis inhibition, and direct inhibition of glutathione-dependent enzymes to induce oxidative stress or ferroptosis.