Glutathione-dependent antioxidant pathway (GSH pathway)

The glutathione-dependent antioxidant pathway is a fundamental cellular defense system centered on the tripeptide glutathione (GSH), which serves as the primary non-protein thiol in mammalian cells [3, 12]. This pathway maintains redox homeostasis by neutralizing reactive oxygen species (ROS) and detoxifying xenobiotics through the coordinated activity of enzymes such as glutathione peroxidase (GPX), glutathione reductase (GR), and glutathione S-transferase (GST) [8, 9]. In normal physiology, it protects cells from oxidative damage and regulates critical processes like protein folding and signal transduction [4, 16]. However, in many cancers, the pathway is significantly upregulated to counteract high metabolic stress and provide resistance against pro-oxidant therapies like chemotherapy and radiation [1, 5, 8]. Consequently, the pathway is a major therapeutic target, with strategies ranging from GSH depletion to induce ferroptosis in tumors to GSH supplementation for treating neurodegenerative and inflammatory diseases [4, 14, 17].

Other names

Glutathione systemGlutathione redox systemGSH-dependent antioxidant systemgamma-glutamyl cycle

Drugs targeting this pathway act by inhibiting glutathione synthesis (e.g., GCL inhibition by BSO), depleting intracellular GSH levels to induce ferroptosis (e.g., APR-246), or inhibiting the cystine/glutamate antiporter (System Xc-) to limit precursor availability [1, 4, 5]. Conversely, antioxidant capacity can be enhanced through the administration of GSH precursors like N-acetylcysteine to mitigate oxidative stress in chronic diseases [11, 14].