Glutathione peroxidase 4

Overview

Glutathione peroxidase 4 (GPX4) is a selenoenzyme in the glutathione peroxidase family that plays a central protective role against oxidative membrane damage by reducing lipid hydroperoxides to their corresponding lipid alcohols. By limiting lipid peroxidation, GPX4 helps maintain membrane integrity and cellular redox homeostasis, particularly in settings where reactive oxygen species, iron, and polyunsaturated lipids converge to drive oxidative injury. Because of this function, GPX4 is a key negative regulator of ferroptosis, an iron-dependent form of regulated cell death characterized by lethal accumulation of lipid peroxides.

In biomedical research, GPX4 is widely studied as both a mechanistic node in disease biology and a therapeutic target. Altered GPX4 activity has been linked to oxidative stress, mitochondrial dysfunction, inflammation, drug resistance, and tumor biology, and it is frequently investigated alongside pathways involving glutathione, solute carrier family 7 member 11, Nuclear factor erythroid 2-related factor 2 (NRF2), and Acyl-CoA synthetase long-chain family member 4 (ACSL4). Pharmacologic inhibition, protein destabilization, or genetic silencing of GPX4 can promote ferroptosis, whereas preservation of GPX4 function can mitigate tissue injury in models of oxidative stress-related disease.

Recent Publications Summary

Recent studies have positioned GPX4 as a major therapeutic target in ferroptosis-based cancer therapy and in diseases marked by oxidative tissue injury. In epithelial ovarian cancer, researchers examined the expression of ATP7B, CTR1, GPX4, 53BP1, p-H2AX, and p-ATM in relation to platinum sensitivity and prognosis, focusing on the interplay between ferroptosis and DNA damage repair in patient outcomes 42593694Aug. In triple-negative breast cancer, a novel azaindole-based GPX4 inhibitor, DA-5, was developed and its binding affinity and enzymatic inhibitory activity against GPX4 were evaluated as part of a strategy to induce ferroptosis for targeted therapy 42048687Apr. In papillary thyroid carcinoma, curcumin was investigated for its ability to induce ferroptosis by regulating GPX4 expression, highlighting GPX4-mediated lipid peroxide control as a mechanism relevant to tumor cell death 42550316Aug.

Several studies focused on protecting tissues by stabilizing GPX4 or preserving its activity to suppress ferroptosis. In cisplatin-induced acute kidney injury, multifunctional polydopamine nanoparticles were reported to alleviate oxidative stress and inhibit ferroptosis by downregulating ACSL4, chelating ferrous ions, and stabilizing GPX4 protein, indicating a combined strategy targeting iron-dependent lipid peroxidation and GPX4 loss 42435348Jul. In diabetic nephropathy, miR-145-5p was investigated as a regulator of high-glucose-induced ferroptosis and tubular epithelial cell injury through the KLF4/SIRT3/GPX4 signaling axis, underscoring GPX4’s role in renal cell injury responses 42494277Jul. In addition, a hyaluronic acid-modified pH-responsive Cu-based nanocascade reactor was reported to enhance cancer chemo-chemodynamic synergistic therapy, with sulfasalazine used to inhibit GPX4 activity and thereby amplify oxidative stress in tumor cells 41855820Mar.

Other reports emphasized post-translational control and gene silencing of GPX4 in cancer progression and ferroptosis induction. In hepatocellular carcinoma, mitochondrial ribosomal protein S30 (MRPS30) was shown to interact with GPX4 and inhibit K48-linked ubiquitination of GPX4, maintaining GPX4 protein stability and thereby suppressing ferroptosis while promoting tumor progression 42542152Aug. Finally, a ferrous-supply-regenerating lipid nanoparticle system was developed to co-deliver GPX4-siRNA and Fe3+, using arachidonic acid-containing nanoparticles to drive ferroptosis for cancer therapy 42528415Jul. Collectively, these studies show GPX4 as a convergent target in ferroptosis regulation, linking glutathione-dependent antioxidant defense, lipid peroxidation control, iron metabolism, and disease-specific therapeutic design across cancer, kidney injury, and platinum responsiveness 42593694Aug42048687Apr42550316Aug42435348Jul42542152Aug41855820Mar42494277Jul42528415Jul.

What Changes, What Holds

1. GPX4 now looks like a tractable node for precision cancer sensitization and prognostic stratification
REINFORCES Ovarian, breast, and thyroid cancer studies extend the established view of GPX4 as a ferroptosis-linked therapeutic target rather than revising it. They sharpen the practical implication that lowering GPX4 activity, or reading out its status alongside DNA damage and platinum-response markers, may help identify tumors more likely to succumb to oxidative membrane damage. The baseline already anticipated this direction, so the new work mainly broadens tumor contexts and strengthens translational interest 42593694Aug42048687Apr.

2. GPX4 preservation remains a kidney-protective strategy, while GPX4 inhibition is being repurposed to intensify tumor oxidative injury
REINFORCES Kidney and cancer nanotherapy reports stay within the baseline account that GPX4 suppression promotes ferroptosis and that preserving GPX4 can limit tissue injury. The renal studies support GPX4 stabilization as part of anti-oxidative rescue in cisplatin injury and diabetic nephropathy, whereas the tumor study uses sulfasalazine to inhibit GPX4 as a way to amplify oxidative stress. Together they refine, rather than overturn, the bidirectional therapeutic logic already established for GPX4 42435348Jul42494277Jul41855820Mar.

3. GPX4 stability emerges as an additional oncogenic control point, but the core ferroptosis model remains intact
REINFORCES MRPS30-dependent protection of GPX4 from K48-linked ubiquitination adds a post-translational mechanism by which tumors can maintain ferroptosis resistance and progression, fitting the baseline’s emphasis on GPX4 destabilization as a way to trigger cell death. The siRNA-plus-iron nanoparticle work likewise reinforces the established therapeutic strategy of suppressing GPX4 to drive ferroptosis. What is new is the detailed mechanism of GPX4 stabilization in hepatocellular carcinoma, not a different biological role for GPX4 42542152Aug42528415Jul.

Overview update candidates: MRPS30-mediated stabilization of GPX4 in hepatocellular carcinoma; GPX4-directed siRNA/iron nanoparticle ferroptosis therapy.