Cellular redox system and glutathione metabolism (GSH metabolism)

The cellular redox system and glutathione metabolism comprise a sophisticated network of enzymes and small molecules that maintain intracellular homeostasis by managing oxidative stress. Central to this system is glutathione (GSH), a tripeptide that acts as a major endogenous antioxidant and a cofactor for various enzymes [2]. Key components include glutamate-cysteine ligase (GCL), which is the rate-limiting enzyme in GSH synthesis, and glutathione peroxidase (GPx), which reduces hydrogen peroxide and lipid hydroperoxides [5]. This system plays a dual role in human health: while it protects normal cells from DNA damage and oxidative injury, its upregulation in cancer cells often confers resistance to chemotherapy and radiation [3]. Therapeutic interventions target this pathway either to replenish antioxidant capacity in neurodegenerative and inflammatory diseases or to induce lethal oxidative stress in malignant cells through glutathione depletion [1]. Recent advances have also highlighted the system's critical role in regulating ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation [4].

Other names

Glutathione metabolic pathwayGSH homeostasisThiol-based redox systemAntioxidant defense systemGSH system

The mechanism of action involves the modulation of intracellular thiol pools and the activity of antioxidant enzymes. Drugs like N-acetylcysteine provide cysteine precursors to increase glutathione synthesis [5], while inhibitors like buthionine sulfoximine target glutamate-cysteine ligase to deplete glutathione and sensitize cells to oxidative stress [1]. Other agents, such as erastin, inhibit the system Xc- transporter, leading to glutathione depletion and the induction of ferroptosis [4].