The host inflammatory response is a crucial determinant of disease outcome and correlates with disease severity in SARS-CoV-2-induced infection, for which there is no treatment to date.Activation of transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) promotes resolution of inflammation and, in parallel, restores cellular redox and protein homeostasis, and facilitates tissue repair.NRF2 can be activated by pharmacological inducers that target Kelch-like ECH-associated protein 1 (KEAP1), the principal negative regulator of NRF2.The available information on pharmacokinetics, pharmacodynamics, safety, and efficacy for the NRF2 activators sulforaphane and bardoxolone methyl (currently in advanced clinical trials for other disease indications) in humans makes them excellent candidates for testing in randomized clinical trials in COVID-19. Acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 is largely the result of a dysregulated host response, followed by damage to alveolar cells and lung fibrosis. Exacerbated proinflammatory cytokines release (cytokine storm) and loss of T lymphocytes (leukopenia) characterize the most aggressive presentation. We propose that a multifaceted anti-inflammatory strategy based on pharmacological activation of nuclear factor erythroid 2 p45-related factor 2 (NRF2) can be deployed against the virus. The strategy provides robust cytoprotection by restoring redox and protein homeostasis, promoting resolution of inflammation, and facilitating repair. NRF2 activators such as sulforaphane and bardoxolone methyl are already in clinical trials. The safety and efficacy information of these modulators in humans, together with their well-documented cytoprotective and anti-inflammatory effects in preclinical models, highlight the potential of this armamentarium for deployment to the battlefield against COVID-19. Acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 is largely the result of a dysregulated host response, followed by damage to alveolar cells and lung fibrosis. Exacerbated proinflammatory cytokines release (cytokine storm) and loss of T lymphocytes (leukopenia) characterize the most aggressive presentation. We propose that a multifaceted anti-inflammatory strategy based on pharmacological activation of nuclear factor erythroid 2 p45-related factor 2 (NRF2) can be deployed against the virus. The strategy provides robust cytoprotection by restoring redox and protein homeostasis, promoting resolution of inflammation, and facilitating repair. NRF2 activators such as sulforaphane and bardoxolone methyl are already in clinical trials. The safety and efficacy information of these modulators in humans, together with their well-documented cytoprotective and anti-inflammatory effects in preclinical models, highlight the potential of this armamentarium for deployment to the battlefield against COVID-19. Numerous clinical observations during the outbreaks of coronaviruses – severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome-related coronavirus (MERS-CoV), and most recently SARS-CoV-2 – convincingly show that, in addition to virus propagation, the host inflammatory response is a crucial determinant of disease outcome [1.Guan W.J. et al.Clinical characteristics of coronavirus disease 2019 in China.N. Engl. J. Med. 2020; 382: 1861-1862Crossref PubMed Scopus (2383) Google Scholar]. A parallel can be drawn with influenza, for which lethality is not associated with the cytolytic action of the pathogen but instead with the inflammatory response orchestrated by the host immune system [2.Galani I.E. Andreakos E. Neutrophils in viral infections: current concepts and caveats.J. Leukoc. Biol. 2015; 98: 557-564Crossref PubMed Scopus (47) Google Scholar]. In the most severe cases of the disease, a cytokine storm (excess production of cytokines) [3.Huang C. et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (4657) Google Scholar] is associated with T cell depletion, pulmonary inflammation, and lung damage. Patients showing acute respiratory distress syndrome (ARDS; see Glossary) and other types of virus-induced pneumonia also present features of macrophage activation syndrome (MAS) [3.Huang C. et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (4657) Google Scholar]. There is also evidence of leukopenia, with a ~twofold decrease in T cell number [4.Qin C. et al.Dysregulation of immune response in patients with COVID-19 in Wuhan, China.Clin. Infect. Dis. 2020; (Published online March 12, 2020. https://doi.org/10.1093/cid/ciaa248)Crossref Google Scholar], which may be the result of pyroptosis, a form of cell death that mainly affects cells of the immune system [5.Fung S.Y. et al.A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses.Emerg. Microbes Infect. 2020; 9: 558-570Crossref PubMed Scopus (46) Google Scholar]. On the other hand, granulocytosis might be partly responsible for the strong burst of superoxide [2.Galani I.E. Andreakos E. Neutrophils in viral infections: current concepts and caveats.J. Leukoc. Biol. 2015; 98: 557-564Crossref PubMed Scopus (47) Google Scholar], a type of reactive oxygen species (ROS) [6.Sies H. Jones D.P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents.Nat. Rev. Mol. Cell Biol. 2020; 21: 363-383Crossref PubMed Scopus (20) Google Scholar], and the additional production of proinflammatory cytokines [7.DeDiego M.L. et al.Inhibition of NF-kappaB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival.J. Virol. 2014; 88: 913-924Crossref PubMed Scopus (0) Google Scholar]. To comprehensively manage the symptoms of COVID-19 (the disease caused by SARS-CoV-2), it is crucial to understand the most appropriate context for introducing an anti-inflammatory therapy to complement an antiviral therapy. Such therapy must control inflammation without altering the ability of the host to mount an efficient adaptive immune response against the virus. We propose that boosting endogenous cellular defenses by targeting the cytoprotective transcription factor NRF2 (gene name NFE2L2) will promote the resolution of COVID-19 associated inflammation and also restore redox homeostasis and facilitate tissue repair. It should be noted that the protein under discussion is distinctly separate from the identically abbreviated nuclear respiratory factor 2 (also known as GA binding protein transcription factor subunit β, gene name GABPB1), a completely different transcription factor involved in mitochondrial biogenesis [8.Jornayvaz F.R. Shulman G.I. Regulation of mitochondrial biogenesis.Essays Biochem. 2010; 47: 69-84Crossref PubMed Google Scholar]. NRF2 is a cap'n'collar (CNC) transcription factor that heterodimerizes with small musculoaponeurotic fibrosarcoma (sMAF) proteins, K, G, or F [9.Otsuki A. Yamamoto M. Cis-element architecture of Nrf2–sMaf heterodimer binding sites and its relation to diseases.Arch. Pharm. Res. 2020; 43: 275-285Crossref PubMed Scopus (0) Google Scholar], or with transcription factors C-JUN and JUND [10.Venugopal R. Jaiswal A.K. Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes.Oncogene. 1998; 17: 3145-3156Crossref PubMed Google Scholar], to bind to antioxidant response elements (AREs), and regulates the transcription of target genes, including those encoding proteins involved in cellular redox homeostasis, detoxification, macromolecular damage repair, and metabolic balance [11.Cuadrado A. et al.Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases.Nat. Rev. Drug Discov. 2019; 18: 295-317Crossref PubMed Scopus (134) Google Scholar]. Under basal conditions, NRF2 interacts with the E3 ligase substrate adapter Kelch-like ECH-associated protein 1 (KEAP1) that targets the transcription factor for ubiquitination and proteasomal degradation [11.Cuadrado A. et al.Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases.Nat. Rev. Drug Discov. 2019; 18: 295-317Crossref PubMed Scopus (134) Google Scholar, 12.Cuadrado A. et al.Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach.Pharmacol. Rev. 2018; 70: 348-383Crossref PubMed Scopus (110) Google Scholar, 13.Hayes J.D. Dinkova-Kostova A.T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism.Trends Biochem. Sci. 2014; 39: 199-218Abstract Full Text Full Text PDF PubMed Scopus (759) Google Scholar] (Figure 1, Key Figure). Electrophiles and ROS (collectively termed inducers) inactivate KEAP1 by modifying specific sensor cysteine residues [14.Dinkova-Kostova A.T. et al.Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants.Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11908-11913Crossref PubMed Scopus (1383) Google Scholar], resulting in NRF2 accumulation and enhanced target gene transcription. NRF2 activity is frequently dysregulated in disease states, including diabetes, liver disease, and inflammatory bowel disease [15.Rabbani P.S. et al.Dysregulation of Nrf2/Keap1 redox pathway in diabetes affects multipotency of stromal cells.Diabetes. 2019; 68: 141-155Crossref PubMed Scopus (7) Google Scholar], and declines with aging [16.Schmidlin C.J. et al.Redox regulation by NRF2 in aging and disease.Free Radic. Biol. Med. 2019; 134: 702-707Crossref PubMed Scopus (36) Google Scholar]. Some of these disease states (e.g., diabetes) and older age are risk factors associated with SARS-CoV-2-induced ARDS [17.Wu C. et al.Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.JAMA Intern. Med. 2020; 180: 1-11Crossref Scopus (739) Google Scholar]. Importantly, activation of NRF2 has been shown to be involved in preserving lung architecture in response to inflammatory cues, and therapeutic effects of NRF2 activation have been reported in animal models of several lung disorders, including respiratory infections and ARDS [18.Liu Q. et al.Role of Nrf2 and its activators in respiratory diseases.Oxidative Med. Cell. Longev. 2019; 2019: 7090534PubMed Google Scholar]. Moreover, single-nucleotide polymorphisms (SNPs) located in the promoter region of NFE2L2 (encoding NRF2) have been implicated in lung disease susceptibility in humans, hence reinforcing NRF2 as therapeutic target for pulmonary diseases [19.Acosta-Herrera M. et al.Common variants of NFE2L2 gene predisposes to acute respiratory distress syndrome in patients with severe sepsis.Crit. Care. 2015; 19: 256Crossref PubMed Scopus (9) Google Scholar,20.Hua C.C. et al.Functional haplotypes in the promoter region of transcription factor Nrf2 in chronic obstructive pulmonary disease.Dis. Markers. 2010; 28: 185-193Crossref PubMed Google Scholar]. NRF2 also plays a role in both the execution and the resolution of inflammation [12.Cuadrado A. et al.Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach.Pharmacol. Rev. 2018; 70: 348-383Crossref PubMed Scopus (110) Google Scholar] by repressing proinflammatory genes such as IL6 and IL1B [21.Kobayashi E.H. et al.Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription.Nat. Commun. 2016; 7: 11624Crossref PubMed Scopus (362) Google Scholar]. This is particularly prominent in lipopolysaccharide (LPS)-stimulated macrophage cells, where the anti-inflammatory immunometabolite itaconate, that accumulates during metabolic reprogramming of these cells, activates NRF2 [22.Mills E.L. et al.Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1.Nature. 2018; 556: 113-117Crossref PubMed Scopus (245) Google Scholar]. Moreover, NRF2 also induces the transcription of several macrophage-specific genes that participate in tissue repair. These include macrophage receptor with collagenous structure (MARCO), a receptor required for bacterial phagocytosis, cluster of differentiation 36 (CD36), a scavenger receptor for oxidized low-density lipoproteins (LDL) [24.Harvey C.J. et al.Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model.Sci. Transl. Med. 2011; 378ra32Crossref PubMed Scopus (176) Google Scholar], and IL-17D [25.Seelige R. et al.The ancient cytokine IL-17D is regulated by Nrf2 and mediates tumor and virus surveillance.Cytokine. 2017; 91: 10-12Crossref PubMed Scopus (5) Google Scholar], which confer protection against viral infections [26.Saddawi-Konefka R. et al.Nrf2 induces IL-17D to mediate tumor and virus surveillance.Cell Rep. 2016; 16: 2348-2358Abstract Full Text Full Text PDF PubMed Google Scholar]. Similarly, NRF2 activation restores redox homeostasis by upregulating glutathione (GSH), NADPH, thioredoxin, thioredoxin reductase, and peroxiredoxin that protect against oxidative stress and favor alternative wound healing versus classical proinflammatory activation of macrophages and other immune cells [27.Brune B. et al.Redox control of inflammation in macrophages.Antioxid. Redox Signal. 2013; 19: 595-637Crossref PubMed Scopus (0) Google Scholar]. The role of NRF2 in viral infections has been investigated in the context of both DNA and RNA viruses. In general, viruses can benefit from either activating or inhibiting NRF2 in host cells [28.Deramaudt T.B. et al.Regulation of oxidative stress by Nrf2 in the pathophysiology of infectious diseases.Med. Mal. Infect. 2013; 43: 100-107Crossref PubMed Scopus (0) Google Scholar]. This might be dependent on factors such as the stage of infection [29.Wyler E. et al.Single-cell RNA-sequencing of herpes simplex virus 1-infected cells connects NRF2 activation to an antiviral program.Nat. Commun. 2019; 10: 4878Crossref PubMed Scopus (6) Google Scholar] or the specific mechanisms of viral propagation – that favor either death of the infected cells and lytic release of virions, or survival of the infected cells with reduction of the inflammatory response to help viral propagation [30.Halder U.C. et al.Cell death regulation during influenza A virus infection by matrix (M1) protein: a model of viral control over the cellular survival pathway.Cell Death Dis. 2011; 2e197Crossref PubMed Scopus (24) Google Scholar]. For human coronavirus HCoV-229E, which is associated with the common cold and pulmonary disease [31.Gorse G.J. et al.Human coronavirus and acute respiratory illness in older adults with chronic obstructive pulmonary disease.J. Infect. Dis. 2009; 199: 847-857Crossref PubMed Scopus (49) Google Scholar], deficiency in expression of the NRF2 target gene glucose-6-phosphate dehydrogenase (G6PDH) increases ROS production and enhances viral gene expression and particle production [32.Wu Y.H. et al.Glucose-6-phosphate dehydrogenase deficiency enhances human coronavirus 229E infection.J. Infect. Dis. 2008; 197: 812-816Crossref PubMed Scopus (40) Google Scholar]. Crucially, the NRF2 pathway has been found to be suppressed in lung biopsies from COVID-19 patients; conversely, pharmacological inducers of NRF2 inhibit the replication of SARS-CoV2 and the inflammatory response [33.Olagnier D.P. et al.Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate.Nat. Commun. 2020; (Published online May 27, 2020. http://dx.doi.org/10.21203/rs.3.rs-31855/v1)Google Scholar]. Interestingly, there is reciprocal crosstalk between NRF2 and NF-κB in inflamed tissues, where innate immune cells are recruited [34.Cuadrado A. et al.Transcription factors NRF2 and NF-kappaB are coordinated effectors of the Rho family, GTP-binding protein RAC1 during inflammation.J. Biol. Chem. 2014; 289: 15244-15258Crossref PubMed Scopus (143) Google Scholar, 35.Lastres-Becker I. et al.Fractalkine activates NRF2/NFE2L2 and heme oxygenase 1 to restrain tauopathy-induced microgliosis.Brain. 2014; 137: 78-91Crossref PubMed Scopus (63) Google Scholar, 36.Boutten A. et al.NRF2 targeting: a promising therapeutic strategy in chronic obstructive pulmonary disease.Trends Mol. Med. 2011; 17: 363-371Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar]. Following infection with SARS-CoV, NF-κB is activated in lungs of mice and in human monocyte macrophages in vitro; conversely, inhibition of NF-κB decreases inflammation and improves survival after SARS-CoV infection in mice [7.DeDiego M.L. et al.Inhibition of NF-kappaB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival.J. Virol. 2014; 88: 913-924Crossref PubMed Scopus (0) Google Scholar,37.Dosch S.F. et al.SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-kappaB pathway in human monocyte macrophages in vitro.Virus Res. 2009; 142: 19-27Crossref PubMed Scopus (33) Google Scholar]. Thus, pharmacological activation of NRF2 might also limit NF-κB-mediated inflammatory processes inflicted in the lung by SARS-CoV-2 infection. The SARS-CoV-2 genome encodes non-structural proteins (nsp) that are required for replication, structural proteins including spike (S), envelope (E), membrane (M), and nucleocapsid (N), and accessory proteins ORF3, 6, 7a, 7b, 8, and 9b that interact with the host cells [38.Zhu N. et al.A novel coronavirus from patients with pneumonia in China, 2019.N. Engl. J. Med. 2020; 382: 727-733Crossref PubMed Scopus (2517) Google Scholar]. The receptor-binding domain (RBD) located in the S protein of SARS-CoV-2 interacts with the angiotensin-converting enzyme 2 (ACE2) of host cells to allow viral entry (Figure 1) [39.Chen Y. et al.Structure analysis of the receptor binding of 2019-nCoV.Biochem. Biophys. Res. Commun. 2020; 525: 135-140Crossref PubMed Scopus (82) Google Scholar]. The use of ACE inhibitors/angiotensin-receptor blockers, which are widely prescribed to patients with cardiovascular pathologies [40.Lopes R.D. et al.Continuing versus suspending angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: impact on adverse outcomes in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the BRACE CORONA trial.Am. Heart J. 2020; 226: 49-59Crossref PubMed Scopus (0) Google Scholar], is currently being considered for COVID-19 (clinical trial numbersi NCT04311177 and NCT04312009 for the use of losartan) because angiotensin II, the target of ACE inhibitors, has vasoconstrictive, proinflammatory, pro-oxidative, and prothrombotic effects [41.Mehta P.K. Griendling K.K. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system.Am. J. Physiol. Cell Physiol. 2007; 292: C82-C97Crossref PubMed Scopus (1226) Google Scholar]. However, these inhibitors alter the balance ACE/ACE2 and increase ACE2 levels, thus potentially increasing the number of docking sites for viral entry [42.Magrone T. et al.Focus on receptors for coronaviruses with special reference to angiotensin-converting enzyme 2 as a potential drug target – a perspective.Endocr. Metab. Immune Disord. Drug Targets. 2020; (Published online April 27, 2020. https://doi.org/10.2174/1871530320666200427112902)Crossref Scopus (8) Google Scholar]. NRF2 deficiency is known to upregulate ACE2, whereas its activator oltipraz reduces ACE2 levels [43.Zhao S. et al.Nrf2 deficiency upregulates intrarenal angiotensin-converting enzyme-2 and angiotensin 1–7 receptor expression and attenuates hypertension and nephropathy in diabetic mice.Endocrinology. 2018; 159: 836-852Crossref PubMed Scopus (0) Google Scholar], suggesting that NRF2 activation might reduce the availability of ACE2 for SARS-CoV-2 entry into the cell (Figure 1). By analogy with other coronaviruses, SARS-CoV-2 is expected to modulate the host translational machinery to favor the generation of its own proteins (Figure 1) [44.Nakagawa K. et al.Viral and cellular mRNA translation in coronavirus-infected cells.Adv. Virus Res. 2016; 96: 165-192Crossref PubMed Scopus (11) Google Scholar]. Host countermeasures to this step include inactivation of eukaryotic initiation factor 2 (eIF2) by two of the three cellular eIF2α kinases, protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK), which are known to be activated in response to SARS-CoV infection [45.Krahling V. et al.Severe acute respiratory syndrome coronavirus triggers apoptosis via protein kinase R but is resistant to its antiviral activity.J. Virol. 2009; 83: 2298-2309Crossref PubMed Scopus (35) Google Scholar]. Interestingly, PKR also has the potential to upregulate the autophagy cargo protein p62, which competes with NRF2 for binding to KEAP1 [46.Komatsu M. et al.The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1.Nat. Cell Biol. 2010; 12: 213-223Crossref PubMed Scopus (1145) Google Scholar] and further promotes the autophagic degradation of KEAP1 [47.Taguchi K. et al.Keap1 degradation by autophagy for the maintenance of redox homeostasis.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 13561-13566Crossref PubMed Scopus (237) Google Scholar], thus activating NRF2 transcriptional activity (Figure 1). Moreover, it has been observed in SARS-CoV infection that host-induced blockade of translation of coronavirus proteins, including the S protein, triggers the unfolded protein response (UPR), activating PERK [48.Chan C.P. et al.Modulation of the unfolded protein response by the severe acute respiratory syndrome coronavirus spike protein.J. Virol. 2006; 80: 9279-9287Crossref PubMed Scopus (71) Google Scholar] that phosphorylates and activates NRF2 [49.Cullinan S.B. et al.Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival.Mol. Cell. Biol. 2003; 23: 7198-7209Crossref PubMed Scopus (759) Google Scholar]. This may thus be one step at which NRF2 can be modulated to reduce the potential of SARS-CoV-2 infection of host cells. Cells infected with RNA viruses recognize viral molecular patterns, especially nucleic acids, by cytoplasmic and endosomal receptors, such as the RNA sensors retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA-5) [50.Loo Y.M. et al.Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity.J. Virol. 2008; 82: 335-345Crossref PubMed Scopus (692) Google Scholar], and the DNA sensor cyclic GMP-AMP synthase (cGAS), which signals through the adaptor protein stimulator of interferon genes (STING) to mediate an appropriate immune response [51.Burdette D.L. et al.STING is a direct innate immune sensor of cyclic di-GMP.Nature. 2011; 478: 515-518Crossref PubMed Scopus (677) Google Scholar]. These innate detection systems activate interferon regulatory factor 3 (IRF3)-mediated transcription of type I and III interferons (IFNs) [51.Burdette D.L. et al.STING is a direct innate immune sensor of cyclic di-GMP.Nature. 2011; 478: 515-518Crossref PubMed Scopus (677) Google Scholar]. Coronavirus infections (including SARS-CoV) have been shown to antagonize STING-mediated host immune systems [52.Sun L. et al.Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling.PLoS One. 2012; 7e30802Crossref PubMed Scopus (0) Google Scholar,53.Chen X. et al.SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING–TRAF3–TBK1 complex.Protein Cell. 2014; 5: 369-381Crossref PubMed Scopus (0) Google Scholar]. Although type I IFNs are crucial for restricting viral replication and spread by activating autocrine and paracrine type I IFN receptor signaling, excessive release of IFNs by infected pulmonary alveolar cells or resident macrophages may exacerbate the pulmonary infiltration of additional monocyte-derived macrophages, further potentiating inflammatory damage [54.Acharya D. et al.Dysregulation of type I interferon responses in COVID-19.Nat. Rev. Immunol. 2020; 20: 397-398Crossref PubMed Scopus (5) Google Scholar]. NRF2 downregulates IFN production, in part by downregulating STING expression [55.Olagnier D. et al.Activation of Nrf2 signaling augments vesicular stomatitis virus oncolysis via autophagy-driven suppression of antiviral immunity.Mol. Ther. 2017; 25: 1900-1916Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar,56.Olagnier D. et al.Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming.Nat. Commun. 2018; 9: 3506Crossref PubMed Scopus (31) Google Scholar] (Figure 1). Therefore, NRF2 may attenuate the inflammatory response to viral infection by preventing excessive production of IFNs. In addition, upregulation of the NRF2-transcriptional target heme oxygenase 1 (HO-1, gene name HMOX1) has been linked to an antiviral response against many viruses including HIV, hepatitis C virus (HCV), hepatitis B virus (HBV), enterovirus 71 (E71), influenza virus, respiratory syncytial virus (RSV), Dengue virus (DENV), and Ebola virus (EBOV) [57.Espinoza J.A. et al.Modulation of antiviral immunity by heme oxygenase-1.Am. J. Pathol. 2017; 187: 487-493Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. HO-1 can mediate antiviral responses by forming a heterodimeric complex with IRF3 [58.Koliaraki V. Kollias G. A new role for myeloid HO-1 in the innate to adaptive crosstalk and immune homeostasis.Adv. Exp. Med. Biol. 2011; 780: 101-111Crossref PubMed Scopus (0) Google Scholar]. With this interaction, IRF3 is phosphorylated and translocated into the nucleus where it induces the expression of type I IFNs (Figure 2). Several other mechanisms have been described for the control of viral infection by HO-1, which can be extrapolated to some extent to SARS-CoV-2. HO-1 catalyzes the degradation of heme into three products, biliverdin, Fe2+, and CO, each with putative anti-SARS-CoV-2 activity. Coronaviruses produce viral proteases – 3C-like proteinase (3CL-pro) and papain-like protease (PLpro) – that process the viral polyproteins and are essential for viral replication [59.Bafna K. et al.Structural similarity of SARS-CoV2 M(pro) and HCV NS3/4A proteases suggests new approaches for identifying existing drugs useful as COVID-19 therapeutics.ChemRxiv. 2020; (Published online April 21, 2020. http://dx.doi.org/10.26434/chemrxiv.12153615)PubMed Google Scholar]. Both 3CL-Pro and PLpro share high homology with other viral proteases [60.Baez-Santos Y.M. et al.The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds.Antivir. Res. 2015; 115: 21-38Crossref PubMed Google Scholar] that are known to be inhibited by biliverdin [61.Zhu Z. et al.Biliverdin inhibits hepatitis C virus nonstructural 3/4A protease activity: mechanism for the antiviral effects of heme oxygenase?.Hepatology. 2010; 52: 1897-1905Crossref PubMed Scopus (57) Google Scholar] (Figure 2). Biliverdin is then expected to inhibit both SARS-CoV-2 3CLpro and PLpro. Free Fe2+ binds to the highly conserved divalent metal-binding pocket of RdRp of HCV, inhibiting its enzymatic activity (Figure 2) [62.Fillebeen C. et al.Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C Virus.J. Biol. Chem. 2005; 280: 9049-9057Crossref PubMed Scopus (80) Google Scholar,63.Fillebeen C. Pantopoulos K. Iron inhibits replication of infectious hepatitis C virus in permissive Huh7.5.1 cells.J. Hepatol. 2010; 53: 995-999Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar]. Because this binding pocket is highly conserved in SARS-CoV-2 [64.Gao Y. et al.Structure of the RNA-dependent RNA polymerase from COVID-19 virus.Science. 2020; 368: 779-782Crossref PubMed Scopus (49) Google Scholar] a similar mechanism may confer NRF2/HO-1-mediated antiviral activity against COVID-19. Furthermore, CO elicits antiviral responses against positive-sense single-stranded RNA (+ssRNA) viruses such as E71 [65.Tung W.H. et al.Enterovirus 71 induces integrin beta1/EGFR-Rac1-dependent oxidative stress in SK-N-SH cells: role of HO-1/CO in viral replication.J. Cell. Physiol. 2011; 226: 3316-3329Crossref PubMed Scopus (0) Google Scholar] and bovine viral diarrhea virus (BVDV9) [66.Ma Z. et al.Carbon monoxide and biliverdin suppress bovine viral diarrhoea virus replication.J. Gen. Virol. 2017; 98: 2982-2992Crossref PubMed Scopus (2) Google Scholar], and this effect is phenocopied by the CO donor, CO-releasing molecule 2 (CORM-2), through a mechanism that depends on the activation of soluble guanylyl cyclase (sGC), which increases the local levels of cGMP and activates protein kinase G (PKG) (Figure 2). In turn, PKG inhibits NADPH oxidase (NOX) [67.Kalyanaraman H. et al.Protein kinase G activation reverses oxidative stress and restores osteoblast function and bone formation in male mice with type 1 diabetes.Diabetes. 2018; 67: 607-623Crossref PubMed Scopus (14) Google Scholar], preventing an increase in ROS levels (Figure 2) that otherwise would contribute to inflammation. If these mechanisms are also mirrored in the context of COVID-19, activation of the NRF2/HO-1 pathway holds promise for mitigating SARS-CoV-2 infection. An important limitation for the development of effective therapies against SARS-Cov-2 is the poor reproducibility of COVID-19 in animal models, most of which do not share relevant physiology, do