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.

Recent Publications Summary

Recent publications have continued to position the Nrf2/GPx4 axis as a central regulator of ferroptosis in diverse oxidative-stress and cancer models. In colorectal cancer, artesunate was reported to overcome oxaliplatin resistance by inducing ferroptosis through inhibition of the CDK5/Nrf2/GPX4 pathway, with CDK5 shown to bind Nrf2, increase its stability, and promote its nuclear translocation; overexpression/silencing experiments supported a CDK5–Nrf2–GPX4 mechanism in resistance 42178429May. In gastric cancer, noni fruit juice was reported to suppress tumor progression and induce ferroptosis via the Nrf2/HO-1-GPX4 axis, alongside increased lipid oxidation and mitochondrial morphological changes in MKN-45 and SNU-216 cells 42132559May. Similarly, Scutellaria barbata-derived exosome-like nanovesicles were found to promote ferroptosis in hepatocellular carcinoma, with reduced SLC7A11/GPX4 expression and mechanistic linkage to inhibition of the Nrf2/SLC7A11/GPX4 pathway 42209785May.

Several studies also described Nrf2/GPx4-axis modulation in neuroprotection and vascular injury. salvianolic acid B was reported to preserve microvascular integrity after cerebral infarction by suppressing ferroptosis through an ACSL4/Nrf2 axis, increasing Nrf2 nuclear translocation and upregulating downstream HO-1 and GPX4 while reducing iron deposition and lipid peroxidation; the Nrf2 inhibitor ML385 attenuated these effects 42186809May. Ginsenoside Rg1 was investigated for protection against PM2.5-induced neurotoxicity by suppressing ferroptosis via the Nrf2/GPx4 axis 41775233Mar. In a related oxidative-stress context, polyethylene glycol-23 glyceryl distearate-based niosomes were shown to induce Nrf2-dependent upregulation of xCT and SVCT2 in keratinocytes, with the Nrf2 activation inhibitor K67 diminishing transporter induction; this study focused on enhanced vitamin C delivery and antioxidant capacity rather than direct GPX4 modulation 42217232May.

Other recent work has used the Nrf2/GPx4 axis as a mechanistic readout for ferroptosis-targeting anticancer strategies. Artesunate-ebselen derivatives were designed as GPX4-targeted ferroptosis inducers in colorectal cancer, and the lead compound 5k was reported to directly bind GPX4, increase reactive oxygen species, disrupt mitochondrial membrane potential, and downregulate GPX4 expression 41855635Mar. In melanoma, saquayamycin B1 was described as causing redox disruption and ROS-dependent cytotoxicity, although the abstract did not specifically assign this effect to the Nrf2/GPx4 axis 42174381May. In breast cancer, a zinc-copper-iron layered double hydroxide nanoplatform combined with sonodynamic therapy was reported to induce ferroptosis through GPX4 inactivation and lipid peroxide accumulation, while also triggering cuproptosis; this study did not specifically focus on Nrf2 but reinforced GPX4 as a key ferroptosis node 41830770Mar.

What Changes, What Holds

1. ferroptosis remains the main functional readout, but the axis is now tied to specific resistance and tumor-suppressive contexts
REINFORCES These studies do not revise the baseline mechanism; they extend it by showing the same Nrf2/GPX4 logic operating in colorectal, gastric, and hepatocellular cancer models. The practical implication is that the axis continues to look like a broadly reusable ferroptosis control node, now with added evidence that it can be exploited to overcome drug resistance or suppress tumor growth 42178429May42132559May.

2. Neurovascular protection still fits the established antioxidant model, while one keratinocyte study broadens the axis-adjacent transporter story
REINFORCES salvianolic acid B and ginsenoside Rg1 strengthen the existing view that Nrf2-driven GPX4 support can limit ferroptotic injury in nonmalignant tissues, including brain and microvasculature 42186809May41775233Mar. The niosome work adds a related but narrower point: Nrf2 can also upregulate xCT and SVCT2 to enhance antioxidant capacity without directly centering GPX4, so it expands the network around the axis rather than changing the axis itself 42217232May.

3. GPX4-targeted ferroptosis induction is being refined as a therapeutic strategy, not redefined as a mechanism
REINFORCES The artesunate-ebselen derivative work and the breast cancer nanoplatform study both reinforce the baseline claim that GPX4 is a key ferroptosis vulnerability in cancer 41855635Mar41830770Mar. What changes is the level of therapeutic engineering: one effort directly targets GPX4, while the other uses a delivery-and-energy modality to inactivate it. The melanoma report is directionally consistent with redox disruption, but it does not specifically establish the Nrf2/GPX4 axis 42174381May.

Overview update candidates: none.