Nrf1 (NFE2L1) Signaling in Homeostasis: Latest Advances


  • Editorial Office ROS



Cardiac regeneration; Ferroptosis; GPx4; Lipid droplet; Longevity; NFE2L1; Nrf1; Nrf2


The nuclear factor E2-related factor 1 (Nrf1 or NFE2L1) is a member of the CNC family of leucine zipper transcription factors, which also includes Nrf2, the most extensively studied transcriptional regulator of antioxidant genes. Like Nrf2, Nrf1 also regulates some antioxidant genes; however, it acts differently from Nrf2 in regulating many other cellular processes. This Cutting-Edge Research Highlights discusses some of the latest research findings on Nrf2 signaling in such biological processes as (1) cardiac regeneration, (2) GPx4-dependent ferroptosis, and (3) prolongevity. These advances have broadened the spectrum of Nrf1 physiological functions.

(First online: February 25, 2023)


  1. Chan JY, Han XL, Kan YW. Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast. Proc Natl Acad Sci USA 1993; 90(23):11371–5. doi:
  2. Sykiotis GP, Bohmann D. Stress-activated cap'n'collar transcription factors in aging and human disease. Sci Signal 2010; 3(112):re3. doi:
  3. Ohtsuji M, Katsuoka F, Kobayashi A, Aburatani H, Hayes JD, Yamamoto M. Nrf1 and Nrf2 play distinct roles in activation of antioxidant response element-dependent genes. J Biol Chem 2008; 283(48):33554–62. doi:
  4. Chan JY, Kwong M, Lu R, Chang J, Wang B, Yen TS, et al. Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-1, results in anemia and embryonic lethality in mice. EMBO J 1998; 17(6):1779–87. doi:
  5. Widenmaier SB, Snyder NA, Nguyen TB, Arduini A, Lee GY, Arruda AP, et al. NRF1 is an ER membrane sensor that is central to cholesterol homeostasis. Cell 2017; 171(5):1094–109 e15. doi:
  6. Radhakrishnan SK, Lee CS, Young P, Beskow A, Chan JY, Deshaies RJ. Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells. Mol Cell 2010; 38(1):17–28. doi:
  7. Zhang Y, Nicholatos J, Dreier JR, Ricoult SJ, Widenmaier SB, Hotamisligil GS, et al. Coordinated regulation of protein synthesis and degradation by mTORC1. Nature 2014; 513(7518):440–3. doi:
  8. 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):2600–16. doi:
  9. Bartelt A, Widenmaier SB, Schlein C, Johann K, Goncalves RLS, Eguchi K, et al. Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity. Nat Med 2018; 24(3):292–303. doi:
  10. Cui M, Atmanli A, Morales MG, Tan W, Chen K, Xiao X, et al. Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance. Nat Commun 2021; 12(1):5270. doi:
  11. Forcina GC, Pope L, Murray M, Dong W, Abu-Remaileh M, Bertozzi CR, et al. Ferroptosis regulation by the NGLY1/NFE2L1 pathway. Proc Natl Acad Sci U S A 2022; 119(11):e2118646119. doi:
  12. Castillo-Quan JI, Steinbaugh MJ, Fernandez-Cardenas LP, Pohl NK, Wu Z, Zhu F, et al. An antisteatosis response regulated by oleic acid through lipid droplet-mediated ERAD enhancement. Sci Adv 2023; 9(1):eadc8917. doi:
  13. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149(5):1060–72. doi:
  14. Pearson KJ, Lewis KN, Price NL, Chang JW, Perez E, Cascajo MV, et al. Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction. Proc Natl Acad Sci USA 2008; 105(7):2325–30. doi:




How to Cite

ROS, E. O. (2023). Nrf1 (NFE2L1) Signaling in Homeostasis: Latest Advances. Reactive Oxygen Species, 13, n7–n9.