Nrf2/GPx4 axis
Nrf2/GPx4 axis
Overview
The Nrf2/GPx4 axis refers to the regulatory relationship between nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor governing antioxidant and cytoprotective gene expression, and glutathione Peroxidase 4 (GPX4), a selenoprotein enzyme that reduces phospholipid hydroperoxides within biological membranes. Together, these two proteins constitute a critical node in the cellular defense against oxidative stress and, most prominently, against ferroptosis — a form of regulated, iron-dependent cell death driven by uncontrolled lipid peroxidation. Under conditions of oxidative challenge, Nrf2 translocates to the nucleus, where it binds antioxidant response elements (AREs) and transcriptionally activates a battery of cytoprotective genes, including GPX4 and the cystine/glutamate transporter subunit SLC7A11 (xCT), which fuels glutathione (GSH) biosynthesis required for GPX4 enzymatic activity. The axis thus occupies a central position in determining whether a cell undergoes ferroptotic death or survives lipid peroxidative insult.
The biological significance of the Nrf2/GPx4 axis extends across a broad spectrum of disease contexts, including cancer, neurodegeneration, ischemia-reperfusion injury, vascular disease, and reproductive toxicology. Its dual nature — protective in normal and stressed tissues, yet exploitable as a therapeutic vulnerability in malignancies dependent on antioxidant signaling for survival — has made it a high-priority target in both drug discovery and mechanistic biomedical research. Pharmacological modulation of this axis, either through activation to protect normal tissue or through suppression to sensitize cancer cells to ferroptosis, is an area of intensive contemporary investigation.
Focus of Latest Publications
Recent studies have examined the Nrf2/GPx4 axis primarily as a ferroptosis-related therapeutic target and as a mechanistic readout of oxidative stress modulation.
Several cancer-focused studies reported that inhibition of the Nrf2/GPX4 pathway promotes ferroptosis. In hepatocellular carcinoma, Scutellaria barbata D. Don exosome-like nanovesicles were reported to promote ferroptosis through Nrf2/SLC7A11/GPX4 pathway inhibition, with associated mitochondrial dysfunction and suppression of mitochondrial markers such as ND1, CYTB, COX1, and TFAM. In colorectal cancer, artesunate was described as overcoming oxaliplatin resistance by inducing ferroptosis through inhibition of the CDK5/Nrf2/GPX4 pathway, linking this axis to chemotherapy resistance. A related medicinal chemistry study on Artesunate-Ebselen derivatives also emphasized GPX4-targeted ferroptosis induction and synergistic antitumor immune activation in colorectal cancer, reinforcing GPX4 as a direct therapeutic node.
Other studies showed that activation or restoration of the Nrf2/GPX4 axis suppresses ferroptosis and protects tissues. Salvianolic acid B was reported to preserve microvascular integrity after cerebral infarction by suppressing pro-ferroptotic mediators such as ACSL4 and TFR1 while enhancing Nrf2 nuclear translocation and upregulating downstream effectors HO-1 and GPX4. Similarly, ginsenoside Rg1 attenuated PM2.5-induced neurotoxicity by suppressing ferroptosis via the Nrf2/GPx4 axis, indicating a neuroprotective role for this pathway under particulate matter–induced oxidative stress. In gastric cancer cells, noni fruit juice was reported to induce ferroptosis via the Nrf2/HO-1-GPX4 axis, showing that modulation of this pathway can be leveraged to drive cell death in tumor settings.
The axis also appeared in studies of metabolic and environmental stress. myricetin was reported to inhibit vascular calcification in a hyperglycemic/Pi model by restoring ferroptosis-related regulators including SLC7A11, GPX4, and FTH1, suggesting that preservation of GPX4 expression may counter oxidative and ferroptotic injury in vascular disease. In male mice, co-exposure to PS-NPs and HFPO-TA potentiated reproductive toxicity through iron dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid peroxidation, with ferroptosis evidenced by GPX4 downregulation and ACSL4 upregulation. These findings place GPX4 at the center of toxicant-induced ferroptotic injury.
The Nrf2 component was also studied independently as a redox and resistance regulator. In situ electroactive bacteria-activated nanozyme therapy for solid tumors was reported to amplify chemodynamic therapy by downregulating the oxidative stress-resistant Nrf2, thereby weakening antioxidant defenses. Saquinavir reduced oxidative stress and decreased Nrf2 protein expression in human lung adenocarcinoma cells. In another cancer study, DGAT1 inhibition induced ferroptosis and enhanced cancer immunotherapy efficacy, with downstream events culminating in GPX4 depletion. These studies collectively support the idea that the Nrf2/GPX4 axis is a convergence point for oxidative stress adaptation, ferroptosis control, and treatment response.
Across the cited literature, the axis was repeatedly linked to cancer immunotherapy, checkpoint inhibitor, and combination strategies involving (neo-)adjuvant chemotherapy, oxaliplatin, cisplatin/fluorouracil, and other antitumor approaches. In this context, GPX4 suppression often served as a mechanistic marker of ferroptosis induction, whereas Nrf2 activation was associated with cytoprotection and resistance to oxidative injury. The pathway therefore functions as both a biomarker and a therapeutic target in diverse disease models, including breast, colorectal, head/neck, melanoma, prostate tumors, liver cancer, and nonmalignant oxidative stress conditions.