Glutathione homeostasis pathways (GSH homeostasis)

Glutathione homeostasis pathways represent the integrated network of biochemical reactions responsible for the synthesis, transport, and redox cycling of glutathione (GSH), the primary intracellular antioxidant (Source: StatPearls, 2023). The pathway is centered on the de novo synthesis of GSH from glutamate, cysteine, and glycine, catalyzed by glutamate-cysteine ligase (GCL) and glutathione synthetase (GSS) (Source: UniProt, P48506). It also includes the recycling of oxidized glutathione (GSSG) back to its reduced form (GSH) by glutathione reductase (GSR) using NADPH as a cofactor (Source: UniProt, P00390). These pathways are essential for protecting cells against oxidative stress, detoxifying electrophilic compounds via glutathione S-transferases (GSTs), and regulating ferroptosis (Source: PubMed, PMID: 30006450). In clinical contexts, GSH depletion is a hallmark of neurodegenerative diseases like Parkinson's, while its upregulation in cancer cells often contributes to chemoresistance and survival under metabolic stress (Source: PubMed, PMID: 23429477). Therapeutic strategies target these pathways either to restore antioxidant capacity (e.g., N-acetylcysteine) or to induce oxidative lethality in tumors by inhibiting GSH synthesis or cystine uptake (e.g., buthionine sulfoximine or erastin) (Source: NIH, 2021).

Other names

Glutathione metabolismGSH redox cycleGlutathione systemGSH-GSSG cycle

Modulation of glutathione levels through precursor supplementation, inhibition of biosynthetic enzymes (e.g., GCLC), or inhibition of cystine/glutamate transport (System Xc-).