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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 &gt;10-fold. Strikingly, the compounds downregulate\n                    <jats:italic>ACE2, TMPRSS2<\/jats:italic>\n                    , and\n                    <jats:italic>XPO1<\/jats:italic>\n                    mRNA and protein, whereby 4OI diminishes STAT3 phosphorylation and represses the\n                    <jats:italic>XPO1<\/jats:italic>\n                    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\u2009&gt;\u20094OI\u2009&gt;\u2009SFN\u2009&gt;\u2009BARD, suggesting that especially BARD restricts hCoV-229E via another, unknown, target. Taken together, these results suggest that \u201cNRF2 activators\u201d can restrict human coronaviruses by targeting an NRF2-independent network involving ACE2, TMPRSS2, and XPO1.\n                  <\/jats:p>","DOI":"10.1038\/s42003-026-09724-6","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T18:04:20Z","timestamp":1771610660000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["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"],"prefix":"10.1038","volume":"9","author":[{"given":"Fakhar H.","family":"Waqas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9697-4894","authenticated-orcid":false,"given":"Leandro","family":"Silva da Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2751-8411","authenticated-orcid":false,"given":"Francisco J.","family":"Zapatero-Belinch\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madalina E.","family":"Carter-Timofte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Lasswitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Demi","family":"van der Horst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"M\u00f6ller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Dahlmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Olmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Geffers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisa","family":"Gerold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6912-0674","authenticated-orcid":false,"given":"David","family":"Olagnier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3434-2311","authenticated-orcid":false,"given":"Frank","family":"Pessler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"9724_CR1","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41579-022-00713-0","volume":"20","author":"MM Lamers","year":"2022","unstructured":"Lamers, M. 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