GPX4

GPX4 Full Name

glutathione peroxidase 4

GPX4 Introduction

GPX4, also known as glutathione peroxidase 4, is a unique selenoprotein that plays a central role in protecting cells from oxidative damage and regulating ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation. Unlike other glutathione peroxidases that reduce hydrogen peroxide and organic hydroperoxides using glutathione as a co-substrate, GPX4 has the distinctive ability to directly reduce lipid hydroperoxides within cellular membranes, thereby preventing the propagation of lipid peroxidation chain reactions. This function is essential for maintaining membrane integrity and preventing the accumulation of toxic lipid peroxides that can trigger ferroptotic cell death. GPX4 is expressed in nearly all mammalian tissues and is particularly abundant in the brain, kidney, and testis, where it protects against oxidative stress and supports normal physiological functions. The enzyme's activity depends on a selenocysteine residue at its active site, which is incorporated during translation through a specialized mechanism involving the SECIS element in the 3'UTR of GPX4 mRNA.

Figure 1. The ferroptotic induced peroxidation of phospholipids is mediated by the cyst(e)ine/GSH/GPX4 regulatory pathway. (Source: Weaver K, et al. 2022)

The critical role of GPX4 in preventing ferroptosis has made it a focal point in the study of various diseases. In cancer, GPX4 expression is frequently upregulated in certain tumors, where it promotes cell survival and therapeutic resistance by inhibiting ferroptosis. Conversely, pharmacological inhibition of GPX4 using compounds such as RSL3 or FIN56 induces ferroptosis in cancer cells, offering a promising strategy for cancer therapy. In neurodegeneration, GPX4 deficiency or dysfunction contributes to neuronal loss in conditions such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, where iron accumulation and lipid peroxidation are prominent features. In kidney injury, GPX4 inactivation promotes ferroptosis of renal tubular cells, exacerbating acute kidney injury and chronic kidney disease. The broad implications of GPX4 in health and disease have spurred intensive research into developing GPX4 modulators for therapeutic intervention in cancer, neurodegeneration, and kidney disease.

Alternate Names for GPX4

GPX4; glutathione peroxidase 4; MCSP; GPx-4; PHGPx; snGPx; GSHPx-4; snPHGPx; phospholipid hydroperoxide glutathione peroxidase, mitochondrial; phospholipid hydroperoxidase; sperm nucleus glutathione peroxidase;

• 1. Weaver K, et al. The Selenoprotein Glutathione Peroxidase 4: From Molecular Mechanisms to Novel Therapeutic Opportunities. Biomedicines. 2022 Apr 13;10(4):891.
  2. Ma T, et al. GPX4-independent ferroptosis-a new strategy in disease's therapy. Cell Death Discov. 2022 Oct 30;8(1):434.