Glutathione Metabolism and Oxidative Stress Responses

Glutathione (GSH) is the most abundant cellular thiol and a critical regulator of redox buffering and detoxification across all domains of life. Synthesised from glutamate, cysteine and glycine via the γ-glutamyl cycle, GSH maintains redox homeostasis by scavenging reactive oxygen species (ROS) and serving as a substrate for glutathione peroxidases and transferases. Its dynamic turnover is governed by synthesis, utilisation and degradation pathways, as well as by the transsulfuration pathway that links methionine metabolism to cysteine provision under stress conditions. In response to oxidative insults, perturbations in GSH levels trigger adaptive transcriptional and post-translational networks, encompassing NRF2 activation, modulation of mitochondrial function and repair of oxidised protein thiols. Dysregulation of GSH metabolism underlies diverse pathologies, from neurodegeneration and cancer to metabolic and inflammatory diseases, highlighting its global significance. Recent advances have revealed novel enzymatic regulators, compartment-specific pools and cross-talk with lipid peroxidation processes, offering new therapeutic possibilities for modulating redox balance and mitigating oxidative damage.

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Glutathione Metabolism and Oxidative Stress Responses publication trend

The graph below shows the total number of articles in glutathione metabolism and oxidative stress responses across all publications each year (not limited to Nature Index journals).

Technical terms

Glutathione (GSH): A tripeptide antioxidant synthesised from glutamate, cysteine and glycine that buffers cellular redox potential and detoxifies reactive species.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen, including superoxide and hydrogen peroxide, which can damage biomolecules.

Glutathione peroxidase 4 (GPX4): A selenium-dependent enzyme that reduces lipid hydroperoxides using GSH as a cofactor, preventing ferroptosis.

Ferroptosis: An iron-dependent form of regulated cell death driven by unchecked lipid peroxidation and insufficient antioxidant capacity.

Transsulfuration pathway: A metabolic route linking methionine to cysteine synthesis, sustaining GSH production during oxidative stress.

References

1. Oxidative Metabolism as a Cause of Lipid Peroxidation in the Execution of Ferroptosis. International Journal of Molecular Sciences (2024).
2. Superoxide Radicals in the Execution of Cell Death. Antioxidants (2022).
3. Methionine Deprivation Reveals the Pivotal Roles of Cell Cycle Progression in Ferroptosis That Is Induced by Cysteine Starvation. Cells (2022).