Glutathione Peroxidase 4 Mechanisms in Cell Death and Disease

Glutathione peroxidase 4 (GPX4) is a unique selenoenzyme that safeguards cellular membranes by reducing lipid hydroperoxides to their corresponding alcohols, using reduced glutathione (GSH) as an electron donor. This activity renders GPX4 the principal inhibitor of ferroptosis, an iron-dependent form of regulated cell death characterised by unchecked lipid peroxidation and accumulation of reactive oxygen species. Beyond its cytosolic form, GPX4 localises to mitochondria and nuclei, where it modulates apoptotic and inflammatory pathways. Dysregulation of GPX4 underpins a spectrum of pathologies: overexpression confers resistance to chemotherapy-induced ferroptosis in cancers, whereas its insufficiency contributes to neurodegenerative and cardiovascular disorders through oxidative damage. Regulatory mechanisms include transcriptional control by factors such as Nrf2, translation via mTOR-mediated signalling, and post-translational modifications—ubiquitination, phosphorylation and succination—that fine-tune enzyme activity and stability. In the tumour microenvironment, targeted inhibition of GPX4 triggers lipid peroxidation and selective cancer cell death, offering a promising therapeutic strategy. Conversely, pharmacological activation or up-regulation of GPX4 can suppress excessive inflammation and protect against tissue injury. The dual roles of GPX4 highlight its global significance as both a biomarker and a versatile drug target, with ongoing efforts to optimise delivery, specificity and combination regimens in diverse disease settings.

Research from Nature Portfolio

Recent studies have demonstrated that tumour-specific activation of GPX4 inhibitors can substantially enhance anticancer efficacy. By engineering a peptide–ferriporphyrin conjugate that self-assembles under acidic conditions in the tumour milieu, researchers achieved improved tumour penetration and endocytosis. This platform exploits an assembly-enhanced binding effect to inhibit GPX4 activity more potently, augmenting oxidative stress via a ferriporphyrin-based Fenton reaction. The result is robust induction of ferroptosis across multiple tumour models, overcoming chemoresistance and illustrating a novel strategy for precise delivery of GPX4-targeted therapies.

Glutathione Peroxidase 4 Mechanisms in Cell Death and Disease publication trend

The graph below shows the total number of articles in glutathione peroxidase 4 mechanisms in cell death and disease across all publications each year (not limited to Nature Index journals).

Technical terms

Ferroptosis: A regulated form of cell death driven by iron-dependent lipid peroxidation.

Lipid peroxidation: Oxidative degradation of polyunsaturated fatty acids in cellular membranes, leading to loss of integrity.

Reactive oxygen species (ROS): Chemically reactive oxygen-containing molecules that can damage proteins, lipids and DNA.

Selenoprotein: A protein that incorporates the amino acid selenocysteine, critical for redox enzyme function.

SLC7A11: A cystine/glutamate antiporter that imports cystine for glutathione synthesis and supports GPX4 activity.

References

1. In vivo assembly enhanced binding effect augments tumor specific ferroptosis therapy. Nature Communications (2024).
2. Low-dose hypomethylating agents cooperate with ferroptosis inducers to enhance ferroptosis by regulating the DNA methylation-mediated MAGEA6-AMPK-SLC7A11-GPX4 signaling pathway in acute myeloid leukemia. Experimental Hematology & Oncology (2024).
3. The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1. Redox Biology (2023).
4. HMGA2 alleviates ferroptosis by promoting GPX4 expression in pancreatic cancer cells. Cell Death & Disease (2024).
5. Activation of Glutathione Peroxidase 4 as a Novel Anti-inflammatory Strategy. Frontiers in Pharmacology (2018).
6. The Selenoprotein Glutathione Peroxidase 4: From Molecular Mechanisms to Novel Therapeutic Opportunities. Biomedicines (2022).
7. Post-Translational Modification of GPX4 is a Promising Target for Treating Ferroptosis-Related Diseases. Frontiers in Molecular Biosciences (2022).