GPX4 [Neurosurgery Wiki]

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====== GPX4 ======

Glutathione peroxidase 4, also known as GPX4, is an [[enzyme]] that in humans is encoded by the GPX4 gene.

GPX4 is a phospholipid hydroperoxidase that protects cells against membrane [[lipid peroxidation]].
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[[Ferroptosis]] is a [[cell death]] mode featured by [[lipid peroxide]] accumulation that can be attenuated by [[GPX4]], yet whether and how [[MYCN]] regulates [[Ferroptosis]] are not fully understood. 

Lu et al. reported [[MYCN]]-amplified NB cells are sensitive to GPX4-targeting [[Ferroptosis]] inducers. Mechanically, MYCN expression reprograms the cellular [[iron metabolism]] by upregulating the expression of [[TFRC]], which encodes [[transferrin receptor 1]] as a key [[iron]] [[transporter]] on the [[cell membrane]]. Further, the increased [[iron]] uptake promotes the accumulation of labile iron pool, leading to enhanced [[lipid peroxide]] production. Consistently, [[TFRC]] overexpression in NB cells also induces selective sensitivity to GPX4 inhibition and [[Ferroptosis]]. Moreover, they found that MYCN fails to alter the general [[lipid metabolism]] and the amount of [[cystine]] imported by System Xc(-) for [[glutathione]] synthesis, both of which contribute to [[Ferroptosis]] in alternative contexts. In conclusion, NB cells harboring [[MYCN]] amplification are prone to undergo [[Ferroptosis]] conferred by [[TFRC]] upregulation, suggesting that [[GPX4]]-targeting [[Ferroptosis]] inducers or [[TFRC]] agonists can be potential strategies in treating MYCN-amplified NB
((Lu Y, Yang Q, Su Y, Ji Y, Li G, Yang X, Xu L, Lu Z, Dong J, Wu Y, Bei JX, Pan C, Gu X, Li B. MYCN mediates TFRC-dependent [[Ferroptosis]] and reveals vulnerabilities in neuroblastoma. Cell Death Dis. 2021 May 19;12(6):511. doi: 10.1038/s41419-021-03790-w. PMID: 34011924.)).