MYCN amplification is tightly associated with the poor prognosis of pediatric [[neuroblastoma]] (NB). The regulation of NB [[cell death]] by MYCN represents an important aspect, as it directly contributes to [[tumor progression]] and therapeutic resistance. However, the relationship between MYCN and cell death remains elusive. [[Ferroptosis]] is a newly identified 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.)).