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.

Key Publications

• Mar Layered double hydroxide nanoplatform synergizes with sonodynamic therapy to induce dual activation of cuproptosis and ferroptosis for breast cancer treatment. (Bioorganic chemistry, 2026, PMID 41830770): "These events synergistically triggered ferroptosis by inactivating glutathione peroxidase 4 (GPX4) and accumulating lipid peroxide, while inducing cuproptosis through Cu2+ overload, mitochondrial dysfunction, tricarboxylic acid cycle disruption and lipoylated dihydrolipoamide acetyltransferase (DLAT) oligomerization."
• Jun DGAT1 Inhibition Induces Ferroptosis and Enhances Cancer Immunotherapy Efficacy. (Cancer research, 2026, PMID 41812065): "These events culminated in glutathione peroxidase 4 depletion and ferroptosis."
• Jun Design, synthesis, and in vitro/in vivo biological evaluation of Artesunate-Ebselen derivatives: GPX4-targeted ferroptosis induction and synergistic antitumor immune activation in colorectal cancer. (Bioorganic chemistry, 2026, PMID 41855635): "Glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis, has emerged as a compelling therapeutic target for colorectal cancer (CRC)."
• Jun In Situ Electroactive Bacteria-Activated Nanozyme for Amplifying Chemodynamic Therapy of Solid Tumors. (Nano letters, 2026, PMID 42170851): "...by downregulating the oxidative stress-resistant nuclear factor erythroid 2-related factor 2, further amplifying CDT."
• Jun Co-exposure to PS-NPs and HFPO-TA potentiates reproductive toxicity via ferroptosis and SLC1A5-Mediated glutamine deprivation in male mice. (Chemico-biological interactions, 2026, PMID 41887313): "Mechanistically, HFPO-TA exposure triggered iron dyshomeostasis, mitochondrial dysfunction, oxidative stress and lipid peroxidation, culminating in ferroptosis evidenced by glutathione peroxidase 4 (GPX4) downregulation and acyl-CoA synthetase long chain family member 4 (ACSL4) upregulation."
• Jun Myricetin inhibits vascular calcification in an in vitro model by modulating ferroptosis-related SLC7A11/GPX4 signaling. (Journal of pharmacological sciences, 2026, PMID 42025374): "Furthermore, myricetin restored the expression of ferroptosis-related regulators, including SLC7A11, GPX4, and FTH1, which were reduced under hyperglycemic/Pi conditions."
• Jun Nuclear Factor Erythroid 2-Related Factor 2-Dependent Ferroptosis Suppression by Salvianolic Acid B Preserves Microvascular Integrity and Reduces Risk Factors for Hemorrhagic Transformation After Cerebral Infarction. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42186809): "At the mechanistic level, Sal B suppressed pro-ferroptotic mediators ACSL4 and TFR1 while enhancing Nrf2 nuclear translocation and upregulating its downstream effectors HO-1 and GPX4."
• Jun Dual-mechanism vitamin C delivery by polyethylene glycol-23 glyceryl distearate-based niosomes via SVCT2 induction and enhanced transdermal penetration. (Drug delivery, 2026, PMID 42217232): "...an enhancer of endogenous antioxidant capacity through nuclear factor erythroid 2-related factor 2 (Nrf2) activation."
• May DIA-based proteomic analysis reveals Scutellaria barbata D. Don Exosome-like nanovesicles promote ferroptosis in HCC through Nrf2/SLC7A11/GPX4 pathway. (Functional & integrative genomics, 2026, PMID 42209785): "Mitochondrial dysfunction involved downregulated ND1, CYTB, COX1 and TFAM suppression, mechanistically associated with Nrf2/SLC7A11/GPX4 pathway inhibition."
• May Downregulation of claudin-2 expression and chemoresistance by saquinavir in human lung adenocarcinoma cells. (European journal of pharmacology, 2026, PMID 42081994): "SQV reduced oxidative stress and expression of nuclear factor erythroid 2-related factor 2 protein expression without altering spheroid size, cell viability, or hypoxic stress."