Regulation, Properties and Functions of Mammalian GPX4: Current Progress and Future Directions

Dear Colleagues,

The unique activity of GPX4 (peroxidation-inhibiting protein; PIP in original report) as a genuine glutathione-dependent inhibitor of lipid peroxidation was reported in 1982.   Already, there was controversy over the possible identity of enzymes with such activity, other contenders being GPX1 (classical glutathione peroxidase) and assorted glutathione-S transferases. The pioneers in this effort, Fulvio Ursini and Matilde Maiorino, were sometimes derided about their inability to purify “native GPX”.  Since that time the name of the enzyme evolved to phospholipid hydroperoxide GPX (PHGPX) and finally to GPX4, with incontrovertible evidence at the time that it was the fourth member of the mammalian family of selenium-dependent glutathione peroxidases.  Remarkable properties and assorted functions of GPX4 have come to light.  GPX4 is fairly unique in its ability to catalyze direct reduction of phospholipid- and cholesterol-derived hydroperoxides to redox-inactive alcohols. GPX4 is a structural component of the midpiece of sperm.  This selenoenzyme is a vital component of mammalian development demonstrated by embryonic lethality in GPX4-KO mice, not observed with knockouts of GPX1, 2 and 3.  Essential roles of selenium in development are attributed to GPX4, SELENOT, and TXNRD1 and 2; for example, substituting a cysteine for selenocysteine in GPX4 resulted in early neurological defects in mice.  GPX4 has also been found to play a role in preventing apoptosis of mammalian cells subjected to a cholesterol hydroperoxide or photodynamic therapy-like oxidative challenge. Some of these functions mentioned derive from a proposed central role of GPX4 in inhibiting lipid peroxidatoin-induced ferroptosis, and are attributed to specific subcellular locations of the enzyme. These findings, while extensive in scope, are likely far from the final word on the remarkable properties and functions of GPX4.

We invite papers for a special issue of Biomolecules based on original research into GPX4 regulation, properties and functions, or related areas of study (e.g. selenium status, ferroptosis, lipid peroxidation, interaction with vitamin E) with a significant focus on GPX4. Short reviews that provide unique commentaries on the future of GPX4 studies or closely related research are also invited.

Dr. Steven Esworthy
Prof. Dr. Albert W. Girotti
Guest Editors

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• GPX4
• selenium
• lipid hydroperoxides
• vitamin E
• ferroptosis
• spermatogenesis