Can Activation of NRF2 Be a Strategy against COVID-19?

Abstract

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.

Keywords: KEAP1; SARS-CoV-2; anti-inflammatory ARDS; bardoxolone methyl; sulforaphane.

Figure 1

Key Figure. Putative Viral Cycle of SARS-CoV2 Highlighting Points of Potential Crosstalk with NRF2 Activation. Steps 1–7 depict the different steps of the viral cycle. (1) Binding of the viral spike (S) protein to ACE2 leads to virion entry. NRF2 has been shown to repress ACE2 gene expression in rats [43]. (2) The viral nucleocapsid is uncoated in the cytoplasm of the host cell. (3) Translation of the viral positive-sense single-stranded RNA (+ssRNA) and cleavage of the translation product into specific viral proteins. Viral RNA inside the host cell activates the DNA/RNA sensor cGAS, which signals through the adaptor STING [117], and induces the expression of type I and III interferons (IFNs). NRF2 represses IFN production by downregulating STING expression [56]. (4) Replication of the viral genome. NRF2 induces the expression of HO-1, generating Fe²⁺ that can bind to the divalent metal-binding pocket of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV2 and inhibit its catalytic activity [63,64]. (5) Translation of structural proteins. Host defense is conducted by double-stranded RNA-activated protein kinase R (PKR), which phosphorylates eIF2 and inhibits protein translation. PKR also phosphorylates p62, thus activating NRF2 upon removal of its repressor KEAP1 by autophagy [118]. Inhibition of protein translation in turn activates the unfolded protein response (UPR). PERK, a crucial Ser/Thr protein kinase in UPR signaling, phosphorylates NRF2, resulting in its stabilization and increased transcriptional activity [49]. (6) Virion assembly. (7) Release of viral particles. Abbreviations: ACE2, angiotensin-converting enzyme 2; eIF2, eukaryotic initiation factor 2; ER, endoplasmic reticulum; ERGIC, ER–Golgi intermediate compartment; HO-1, heme oxygenase 1; IFN, interferon; KEAP1, Kelch-like ECH-associated protein 1; NRF2, nuclear factor erythroid 2 p45-related factor 2; PERK, PKR-like endoplasmic reticulum kinase; P, phosphorylation; PKR, protein kinase R; STING, stimulator of interferon genes. Figure generated with Biorender (https://biorender.com/).

Figure 2

Antiviral Activity of HO-1, a Target of NRF2. HO-1 catalyzes the degradation of heme into carbon monoxide (CO), Fe²⁺, and biliverdin. Free Fe²⁺ is expected to bind to the highly conserved divalent metal-binding pocket of the viral RNA-dependent RNA polymerase (RdRp). Carbon monoxide activates soluble guanylyl cyclase (sGC) to generate cGMP, thus activating protein kinase G (PKG), which inhibits NAPDH oxidases (NOX), preventing an increase in reactive oxygen species (ROS). By inhibiting the SARS-CoV-2 proteases 3CLpro and PLpro, biliverdin is expected to suppress the proteolytic maturation of viral polypeptides. Heterodimerization of HO-1 with IRF3 facilitates the phosphorylation and nuclear translocation of IRF3 and the induction of type I IFN gene expression. Abbreviations, HO-1, heme oxygenase 1; IFN, interferon; ISRE, interferon-sensitive response element; IRF3, interferon regulatory factor 3; NRF2, nuclear factor erythroid 2 p45-related factor 2; P, phosphorylation. Figure generated with Biorender (https://biorender.com/).