Ferroptosis Regulation by the NGLY1/NFE2L1 Pathway

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2022 Mar 10

PMID 35271393

Authors

Giovanni C Forcina

Lauren Pope

Magdalena Murray

Wentao Dong

Monther Abu-Remaileh

Carolyn R Bertozzi

Scott J Dixon

Affiliations

Soon will be listed here.

Abstract

SignificanceFerroptosis is an oxidative form of cell death whose biochemical regulation remains incompletely understood. Cap'n'collar (CNC) transcription factors including nuclear factor erythroid-2-related factor 1 (NFE2L1/NRF1) and NFE2L2/NRF2 can both regulate oxidative stress pathways but are each regulated in a distinct manner, and whether these two transcription factors can regulate ferroptosis independent of one another is unclear. We find that NFE2L1 can promote ferroptosis resistance, independent of NFE2L2, by maintaining the expression of glutathione peroxidase 4 (GPX4), a key protein that prevents lethal lipid peroxidation. NFE2L2 can also promote ferroptosis resistance but does so through a distinct mechanism that appears independent of GPX4 protein expression. These results suggest that NFE2L1 and NFE2L2 independently regulate ferroptosis.

Citing Articles

Thirty years of NRF2: advances and therapeutic challenges.

Zhang D Nat Rev Drug Discov. 2025; .

PMID: 40038406 DOI: 10.1038/s41573-025-01145-0.

Aminophylline targets miR-128-3p/Slc7a11 axis to attenuate neuronal ferroptosis after traumatic brain injury.

Manrui L, Xu Y, Liu J, Zhang X, Yuan R, Sun Y Cell Mol Life Sci. 2025; 82(1):87.

PMID: 39985589 PMC: 11846823. DOI: 10.1007/s00018-025-05601-3.

Broadening horizons: research on ferroptosis in lung cancer and its potential therapeutic targets.

Gao G, Zhang X Front Immunol. 2025; 16:1542844.

PMID: 39917300 PMC: 11799241. DOI: 10.3389/fimmu.2025.1542844.

Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways.

Hickey K, Panov A, Whelan E, Schafer T, Mizrak A, Kopito R Proc Natl Acad Sci U S A. 2024; 121(50):e2417390121.

PMID: 39636856 PMC: 11648907. DOI: 10.1073/pnas.2417390121.

Ferroptosis: mechanisms and therapeutic targets.

Zhou Q, Meng Y, Le J, Sun Y, Dian Y, Yao L MedComm (2020). 2024; 5(12):e70010.

PMID: 39568772 PMC: 11577302. DOI: 10.1002/mco2.70010.

References

Chan K, Lu R, Chang J, Kan Y . NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc Natl Acad Sci U S A. 1996; 93(24):13943-8. PMC: 19474. DOI: 10.1073/pnas.93.24.13943. View

Eggler A, Small E, Hannink M, Mesecar A . Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1. Biochem J. 2009; 422(1):171-80. PMC: 3865926. DOI: 10.1042/BJ20090471. View

Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R . Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2015; 63(1):173-84. PMC: 4688087. DOI: 10.1002/hep.28251. View

Iyer S, Mast J, Tsang H, Rodriguez T, DiPrimio N, Prangley M . Drug screens of deficiency in worm and fly models reveal catecholamine, NRF2 and anti-inflammatory-pathway activation as potential clinical approaches. Dis Model Mech. 2019; 12(11). PMC: 6899034. DOI: 10.1242/dmm.040576. View

Jiang X, Stockwell B, Conrad M . Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021; 22(4):266-282. PMC: 8142022. DOI: 10.1038/s41580-020-00324-8. View

Tarangelo A, Magtanong L, Bieging-Rolett K, Li Y, Ye J, Attardi L . p53 Suppresses Metabolic Stress-Induced Ferroptosis in Cancer Cells. Cell Rep. 2018; 22(3):569-575. PMC: 5791910. DOI: 10.1016/j.celrep.2017.12.077. View

Leu J, Murphy M, George D . Functional interplay among thiol-based redox signaling, metabolism, and ferroptosis unveiled by a genetic variant of . Proc Natl Acad Sci U S A. 2020; 117(43):26804-26811. PMC: 7604449. DOI: 10.1073/pnas.2009943117. View

Fan Z, Wirth A, Chen D, Wruck C, Rauh M, Buchfelder M . Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis. 2017; 6(8):e371. PMC: 5608917. DOI: 10.1038/oncsis.2017.65. View

Inde Z, Rodencal J, Dixon S . Quantification of drug-induced fractional killing using high-throughput microscopy. STAR Protoc. 2021; 2(1):100300. PMC: 7829341. DOI: 10.1016/j.xpro.2021.100300. View

10.

Lu S . Glutathione synthesis. Biochim Biophys Acta. 2012; 1830(5):3143-53. PMC: 3549305. DOI: 10.1016/j.bbagen.2012.09.008. View

11.

Takahashi N, Cho P, Selfors L, Kuiken H, Kaul R, Fujiwara T . 3D Culture Models with CRISPR Screens Reveal Hyperactive NRF2 as a Prerequisite for Spheroid Formation via Regulation of Proliferation and Ferroptosis. Mol Cell. 2020; 80(5):828-844.e6. PMC: 7718371. DOI: 10.1016/j.molcel.2020.10.010. View

12.

Wu J, Minikes A, Gao M, Bian H, Li Y, Stockwell B . Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature. 2019; 572(7769):402-406. PMC: 6697195. DOI: 10.1038/s41586-019-1426-6. View

13.

Dirac-Svejstrup A, Walker J, Faull P, Encheva V, Akimov V, Puglia M . DDI2 Is a Ubiquitin-Directed Endoprotease Responsible for Cleavage of Transcription Factor NRF1. Mol Cell. 2020; 79(2):332-341.e7. PMC: 7369636. DOI: 10.1016/j.molcel.2020.05.035. View

14.

Lehrbach N, Breen P, Ruvkun G . Protein Sequence Editing of SKN-1A/Nrf1 by Peptide:N-Glycanase Controls Proteasome Gene Expression. Cell. 2019; 177(3):737-750.e15. PMC: 6574124. DOI: 10.1016/j.cell.2019.03.035. View

15.

Leung L, Kwong M, Hou S, Lee C, Chan J . Deficiency of the Nrf1 and Nrf2 transcription factors results in early embryonic lethality and severe oxidative stress. J Biol Chem. 2003; 278(48):48021-9. DOI: 10.1074/jbc.M308439200. View

16.

Kuang F, Liu J, Xie Y, Tang D, Kang R . MGST1 is a redox-sensitive repressor of ferroptosis in pancreatic cancer cells. Cell Chem Biol. 2021; 28(6):765-775.e5. DOI: 10.1016/j.chembiol.2021.01.006. View

17.

Yang K, Huang R, Fujihira H, Suzuki T, Yan N . N-glycanase NGLY1 regulates mitochondrial homeostasis and inflammation through NRF1. J Exp Med. 2018; 215(10):2600-2616. PMC: 6170171. DOI: 10.1084/jem.20180783. View

18.

Kang Y, Mockabee-Macias A, Jiang C, Falzone A, Prieto-Farigua N, Stone E . Non-canonical Glutamate-Cysteine Ligase Activity Protects against Ferroptosis. Cell Metab. 2020; 33(1):174-189.e7. PMC: 7839835. DOI: 10.1016/j.cmet.2020.12.007. View

19.

Vomund S, Schafer A, Parnham M, Brune B, von Knethen A . Nrf2, the Master Regulator of Anti-Oxidative Responses. Int J Mol Sci. 2017; 18(12). PMC: 5751370. DOI: 10.3390/ijms18122772. View

20.

Yoshida Y, Asahina M, Murakami A, Kawawaki J, Yoshida M, Fujinawa R . Loss of peptide:-glycanase causes proteasome dysfunction mediated by a sugar-recognizing ubiquitin ligase. Proc Natl Acad Sci U S A. 2021; 118(27). PMC: 8271764. DOI: 10.1073/pnas.2102902118. View