Glutathione peroxidase 3 (GPX3) (GPX3)

Glutathione peroxidase 3 (GPX3) is a secreted selenoprotein that serves as the primary antioxidant enzyme in human plasma. It belongs to the glutathione peroxidase family and is unique as the only extracellular member, primarily synthesized in the proximal convoluted tubule of the kidney (UniProt P22352; NCBI Gene 2878). GPX3 plays a critical role in maintaining redox homeostasis by catalyzing the reduction of hydrogen peroxide and organic hydroperoxides into water and alcohols, respectively, using reduced glutathione as a cofactor (Brigelius-Flohé & Maiorino, 2013). In clinical contexts, GPX3 is frequently characterized as a tumor suppressor; its expression is often silenced via promoter hypermethylation in various malignancies, including prostate, thyroid, and colorectal cancers (Yu et al., 2007). Furthermore, deficiency in GPX3 is strongly associated with increased risk of cardiovascular diseases, stroke, and chronic kidney disease due to elevated systemic oxidative stress (Jin et al., 2011). While there are currently no FDA-approved drugs that specifically target GPX3 mRNA, therapeutic strategies under investigation include mRNA-based replacement therapies to restore expression in deficient states and the use of small-molecule mimetics like ebselen to replicate its enzymatic function (Sies & Parnham, 2020).

Other names

Plasma glutathione peroxidaseExtracellular glutathione peroxidaseGPx-PGSHPx-3GPX-3

GPX3 mRNA-based therapies aim to restore the expression of the glutathione peroxidase 3 protein in tissues where it has been silenced or downregulated. The resulting protein catalyzes the reduction of hydrogen peroxide and lipid hydroperoxides, thereby protecting cells and the extracellular matrix from oxidative damage. Small molecule mimetics like ebselen act as pharmacological substitutes for the enzyme's activity, while selenium supplements provide the essential trace element required for the translation of the endogenous mRNA into the functional selenoprotein.