NRF2 activators and the inhibitor of nuclear export, selinexor, restrict coronaviruses by targeting a network involving ACE2, TMPRSS2, and XPO1 through an NRF2-independent mechanism

  • Commun Biol. 2026 Feb 20;9(1):384. doi: 10.1038/s42003-026-09724-6.
Fakhar H Waqas  1  2 ,  Leandro Silva da Costa  3 ,  Francisco J Zapatero-Belinchón  4  5 ,  Madalina E Carter-Timofte  3 ,  Lisa Lasswitz  4 ,  Demi van der Horst  3  6 ,  Rebecca Möller  4  7 ,  Julia Dahlmann  8  9 ,  Ruth Olmer  8  9 ,  Robert Geffers  10 ,  Gisa Gerold  4  11 ,  David Olagnier  3 ,  Frank Pessler  12  13  14
Affiliations
  • 1. Research Group Biomarkers for Infectious Diseases, TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany.
  • 2. Research Group Biomarkers for Infectious Diseases, Helmholtz Centre for Infection Research, Braunschweig, Germany.
  • 3. Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • 4. Institute of Biochemistry & Research Center of Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
  • 5. Gladstone Infectious Disease Institute, Gladstone Institutes, San Francisco, USA.
  • 6. Department of One Health Virology, Wageningen Bioveterinary Research, Wageningen University & Research, Lelystad, The Netherlands.
  • 7. Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
  • 8. Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), REBIRTH-Research Center for Translational and Regenerative Medicine, Hannover Medical School, Hannover, Germany.
  • 9. Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany.
  • 10. Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
  • 11. Institute of Virology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Innsbruck, Austria.
  • 12. Research Group Biomarkers for Infectious Diseases, TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany. [email protected].
  • 13. Research Group Biomarkers for Infectious Diseases, Helmholtz Centre for Infection Research, Braunschweig, Germany. [email protected].
  • 14. Centre for Individualised Infection Medicine, Hannover, Germany. [email protected].
PMID: 41721027 DOI: 10.1038/s42003-026-09724-6
Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2) plays important roles in Antiviral host cell defenses. We assessed the potential of the NRF2 activators 4-octyl itaconate (4OI), bardoxolone (BARD), and sulforaphane (SFN), and the exportin-1 (XPO1) blocker selinexor (SEL) to inhibit highly pathogenic (SARS-CoV-2) and seasonal (hCoV-229E) coronaviruses in cellular models. We find that NRF2 knock-out enhances Infection by both viruses, but that the compounds restrict these viruses in a largely NRF2-independent manner. 4OI and SEL are most effective against SARS-CoV-2 when added to media before Infection, and they reduce cell entry of SARS-CoV-1 and -2 spike protein VSV pseudotypes >10-fold. Strikingly, the compounds downregulate ACE2, TMPRSS2, and XPO1 mRNA and protein, whereby 4OI diminishes STAT3 phosphorylation and represses the XPO1 gene promoter. 4OI dramatically reduces ACE2 half-life, which requires ubiquitin E3 Ligases NEDD4L and MDM2, but is mediated by the lysosomal pathway. XPO1 knock-down reduces CoV-229E replication and reveals that efficacy of the compounds against CoV-229E depends on XPO1 expression in the order SEL > 4OI > SFN > BARD, suggesting that especially BARD restricts hCoV-229E via another, unknown, target. Taken together, these results suggest that "NRF2 activators" can restrict human coronaviruses by targeting an NRF2-independent network involving ACE2, TMPRSS2, and XPO1.

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