[9][unreliable source] Mammalian GPX1, GPX2, GPX3, and GPX4 (this protein) have been shown to be selenium-containing enzymes, whereas GPX6 is a selenoprotein in humans with cysteine-containing homologues in rodents.

In selenoproteins, the amino acid selenocysteine is inserted in the nascent polypeptide chain during the process of translational recoding of the UGA stop codon.

During the catalytic cycle of GPX4, the active selenol (-SeH) is oxidized by peroxides to selenenic acid (-SeOH), which is then reduced with glutathione (GSH) to an intermediate selenodisulfide (-Se-SG).

In mouse and rat, three distinct GPX4 isoforms with different subcellular localization are produced through alternative splicing and transcription initiation; cytosolic GPX4, mitochondrial GPX4 (mGPX4), and nuclear GPX4 (nGPX4).

[15] Knockout studies with GPX1, GPX2, or GPX3 deficient mice showed that cytosolic GPX4 is so far the only glutathione peroxidase that is indispensable for embryonic development and cell survival.

Additionally, the R152H mutation in GPX4 is involved in the development of Sedaghatian-type spinal metaphyseal dysplasia, a rare and fatal disease in newborn babies.