Glutathione metabolism and oxidative stress pathway (GSH pathway) (GSH pathway)

The glutathione and oxidative stress pathways are fundamental cellular systems responsible for maintaining redox homeostasis and protecting cells from damage caused by reactive oxygen species (ROS) and electrophilic compounds (Source: NIH, PubChem). The central component is glutathione (GSH), a tripeptide that acts as a potent antioxidant by donating reducing equivalents to neutralize free radicals (Source: StatPearls). This pathway involves a suite of enzymes, including glutathione peroxidases (GPX) for peroxide detoxification, glutathione reductase (GSR) for recycling oxidized glutathione (GSSG), and glutathione S-transferases (GST) for xenobiotic conjugation (Source: UniProt). Dysregulation of these pathways is a hallmark of various pathologies; for example, oxidative stress is a primary driver of neurodegeneration, while many cancers upregulate glutathione synthesis to survive high metabolic stress and resist chemotherapy (Source: PubMed, PMC4684116). Pharmacological intervention typically aims to either replenish GSH levels using precursors like N-acetylcysteine to treat toxicity or to deplete GSH using inhibitors like buthionine sulfoximine to sensitize cancer cells to treatment (Source: ClinicalTrials.gov). Additionally, targeting specific transporters like the cystine/glutamate antiporter (System Xc-) has emerged as a strategy to induce ferroptosis in tumor cells (Source: Nature). Overall, the glutathione system serves as a master regulator of the cellular redox environment and a key therapeutic node in oncology and neurology (Source: PubMed).

Other names

Glutathione systemRedox homeostasis pathwayGSH/GSSG systemGlutathione-mediated detoxificationOxidative stress response pathway

Drugs modulate this pathway by acting as glutathione precursors, inhibiting rate-limiting enzymes like glutamate-cysteine ligase, blocking cystine transporters, or mimicking antioxidant enzymes to restore or disrupt redox balance.