Glutathione Peroxidase 4 (GPX4)

Overview

glutathione peroxidase 4 (GPX4) is a selenoprotein enzyme that plays a central role in cellular antioxidant defense by reducing lipid hydroperoxides to non-toxic lipid alcohols. By limiting lipid peroxidation, GPX4 helps preserve membrane integrity and protects cells from oxidative damage. Because of this function, GPX4 is widely regarded as a key suppressor of ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxide accumulation.

In biomedical research, GPX4 is frequently studied as both a mechanistic marker and a therapeutic target in cancer, kidney disease, and inflammatory injury. Many recent studies have focused on pathways that regulate GPX4 expression or activity, including the Nrf2/GPX4/eNOS signaling pathway, the System Xc−-GSH-GPX4 axis, and interactions with SLC7A11, Yes-associated protein 1 (YAP1), Wnt/β-catenin, and oxidative stress networks. Because GPX4 sits at the center of ferroptosis control, changes in its abundance or activity are often used to indicate whether a treatment promotes or suppresses ferroptotic cell death.

Recent Publications Summary

Recent studies have continued to position GPX4 as a central regulator of ferroptosis across diverse disease and therapeutic contexts. In cardiomyocytes exposed to lapatinib, transcriptomic analysis identified GPX4 among ferroptosis-associated differentially expressed genes, and follow-up experiments showed that lapatinib markedly suppressed GPX4 protein expression while increasing ATF4, ROS accumulation, Fe²⁺ levels, and mitochondrial dysfunction, consistent with ferroptotic injury 42496814Jul. In a hypoxic pulmonary edema model, multi-omics profiling likewise found significant GPX4 downregulation in lung tissue, with single-cell RNA sequencing implicating pulmonary endothelial cells as a key site of dysregulation; functional studies showed that GPX4 deficiency exacerbated ROS accumulation, ferroptosis, and neutrophil extracellular trap formation, whereas GPX4 overexpression mitigated these effects 42115527May.

Several publications explored GPX4 as a therapeutic target in cancer nanomedicine and combination treatment strategies. In hepatocellular carcinoma, a co-assembled iron nanocomposite promoted ferroptosis-photochemotherapy by depleting glutathione and downregulating GPX4 and SLC7A11, increasing lipid peroxidation and enhancing immunogenic cell death; in vivo, this approach improved anti-PD-L1 efficacy and induced prolonged immunological memory 42133129May. A separate GPC3-targeted nanocarrier for HCC combined violet phosphorus nanoparticles with RSL3 and sulfasalazine, aiming to intensify ferroptosis-based photothermal therapy, while another exosomal platform for triple-negative breast cancer used sorafenib and endogenous microRNAs to sensitize ferroptosis through GPX4 suppression, lipid peroxidation, and mitochondrial dysfunction 42027106Apr42030227Apr. Additional TNBC studies reported that sorafenib-quercetin nanoparticles enhanced ferroptosis by downregulating GPX4 and countering hypoxia-driven resistance through HIF-1α and HK-II suppression, and that manganese-based nanozyme probes enabled GPX4 monitoring alongside ferroptosis induction 41946426Apr41979062Apr.

Other reports linked GPX4 modulation to ferroptosis sensitivity in nonmalignant disease and natural-product screening. In diabetic nephropathy, recombinant ADAMTS13 activated the Nrf2/GPX4 signaling pathway, reduced ROS generation, inhibited mitophagy and ferroptosis, and ameliorated renal injury in mice 41912450Mar. In neuroprotection research, compounds isolated from Astragalus complanatus seeds, including (+)-pinoresinol and desoxyrhapontigenin, protected HT22 cells from RSL3-induced ferroptosis by acting on the System Xc−-GSH-GPX4 axis and upregulating SLC7A11 mRNA 42096616May. In cancer immunotherapy, lipophilic statins were shown to deplete GPX4 by interfering with mevalonate-dependent selenoprotein synthesis, thereby promoting ferroptosis and sensitizing melanoma and colorectal cancer cells to immune checkpoint blockade 41423587Dec.

What Changes, What Holds

1. GPX4 remains a central ferroptosis node, but its loss now appears to drive organ-specific injury programs beyond lipid damage alone
REINFORCES Lapatinib-associated cardiomyocyte injury and hypoxic lung edema both fit the established view of GPX4 as a suppressor of ferroptosis, with reduced GPX4 tracking ROS rise, iron stress, and mitochondrial dysfunction 42496814Jul42115527May. What is added is not a new role but a stronger sense that GPX4 failure can sit upstream of broader tissue injury phenotypes, including neutrophil extracellular trap formation in lung disease, while the baseline account of ferroptosis control remains intact.

2. GPX4 suppression is being used more explicitly as a lever for ferroptosis-based cancer combination therapy
REINFORCES These studies extend the existing therapeutic framing of GPX4 in cancer by showing that downregulating it can be deliberately paired with phototherapy, immunotherapy, and nanodelivery to intensify ferroptotic killing 42133129May42027106Apr. That does not alter the baseline mechanism; it sharpens the practical implication that GPX4 is not just a biomarker of ferroptosis but a manipulable resistance node in hepatocellular carcinoma and triple-negative breast cancer.

3. GPX4-linked ferroptosis control is now being pushed into nonmalignant protection and drug-repurposing settings
REINFORCES Recombinant ADAMTS13 and natural products both act through the same System Xc−-GSH-GPX4 or Nrf2/GPX4 logic already highlighted in the Overview, reinforcing GPX4 as a protective checkpoint in kidney and neuronal injury 41912450Mar42096616May. The statin finding adds a complementary therapeutic angle by showing that depleting GPX4 can also be exploited to sensitize tumors to immune checkpoint blockade 41423587Dec, but that still extends rather than overturns the established ferroptosis framework.

Overview update candidates: GPX4-linked NET formation in hypoxic pulmonary edema; deliberate GPX4 suppression as a combination strategy in cancer nanomedicine; GPX4-protective signaling in diabetic nephropathy and neuroprotection.