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, 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.

Focus of Latest Publications

Recent publications have repeatedly positioned GPX4 as a major determinant of ferroptosis sensitivity across diverse disease models and therapeutic platforms.

In diabetic kidney disease and diabetic nephropathy, GPX4 was described as part of protective antioxidant signaling. One study reported that recombinant human ADAMTS13 ameliorated diabetic nephropathy by activating the Nrf2/GPX4/eNOS signaling pathway, reducing ROS generation, inhibiting mitophagy, and suppressing ferroptosis in diabetic nephropathy mice. Another study in early diabetic kidney disease found increased iron deposition, reduced GPX4 expression, lipid peroxide accumulation, and mitochondrial structural damage in patient tissue and an early DKD rat model, supporting the idea that GPX4 loss is associated with renal ferroptotic injury. A related renal study also linked GPX4 to protection against tubular injury, reinforcing its role as a marker of oxidative stress resistance in kidney disease.

Several cancer studies used GPX4 as a ferroptosis readout or therapeutic target. In triple-negative breast cancer, sorafenib-based and nanoplatform-based strategies were reported to induce ferroptosis through GPX4 suppression, lipid peroxidation, mitochondrial dysfunction, and depletion of glutathione (GSH). A bioinspired exosomal nanoplatform combining sorafenib and microRNA delivery was described as sensitizing ferroptosis and inducing immunoactivation through GPX4 downregulation. Another study using lipophilic statins reported that simvastatin depleted GPX4 in vivo and promoted ferroptosis, thereby sensitizing cancer cells to checkpoint inhibitor. In colorectal cancer, QD394 treatment decreased GSH, SLC7A11/xCT, and GPX4 while increasing malondialdehyde (MDA) and lipid ROS, consistent with ferroptosis induction. In lung adenocarcinoma, artesunate reversed gefitinib resistance by promoting Fe2+ accumulation, ROS formation, and MDA production while suppressing SLC7A11 and GPX4. In hepatocellular carcinoma, multiple nanomedicine studies used GPX4 downregulation as part of ferroptosis-photochemotherapy or ferroptosis/immunotherapy strategies, including systems based on CaO2 nanoparticles, Chlorin e6 (Ce6), and GPC3-targeted nanodelivery system designs.

GPX4 was also implicated in inflammatory and hypoxia-related pathology. A study on hypoxic pulmonary edema reported that hypoxia-induced GPX4 suppression promoted ferroptotic cell death and contributed to neutrophil extracellular trap (NET)-associated inflammation, identifying GPX4 as a critical therapeutic target. In this context, GPX4 downregulation was presented as a central event linking ferroptosis to NET-driven pathology. This reinforces the broader concept that GPX4 is not only a cancer target but also a mediator of tissue injury in hypoxic and inflammatory settings.

Other studies examined GPX4 in ferroptosis-regulating natural products and biomaterials. Lignans and stilbenes from Astragalus complanatus seeds were reported to inhibit ferroptosis by acting on the System Xc−-GSH-GPX4 axis and upregulating SLC7A11 mRNA. A cinnamaldehyde-based self-assembled nanodrug depleted GSH, downregulated GPX4, increased lipid peroxidation, and induced both apoptosis and ferroptosis. A calcium-overloaded composite nanomaterial similarly reduced GSH and GPX4, increased Fe2+ and oxidative stress, and aggravated mitochondrial damage. In another study, a manganese-based nanozyme probe was used for ferroptosis induction and GPX4 monitoring, highlighting GPX4 as a biomarker for tracking ferroptotic responses in real time.

Across these studies, GPX4 consistently functioned as a convergence point for redox control, lipid peroxide detoxification, and ferroptosis regulation. Its suppression generally correlated with increased lipid peroxidation, mitochondrial injury, and cell death, whereas its activation or preservation was associated with cytoprotection in renal and other injury models. The recurring involvement of SLC7A11, GSH, FTH1, ASCL4, CCND1, CTSB, NOX4, TFRC, HIF1A, TGFB1, YAP1, and Wnt/β-catenin pathway components reflects the broad network context in which GPX4 is studied.