Figure 5.

Nrf2-targeted HO-1 antiviral activity. Nrf2-targeted HO-1 catalyzes the enzymatic degradation of heme into CO, Fe²⁺, and biliverdin. CO activates sGC to generate cGMP, which allows PKG to inhibit ROS production via NADPH oxidase (NOX), which can prevent the exacerbation of oxidative stress. Free Fe²⁺ released from heme binds to the viral RdRp divalent metallic binding site to inhibit viral replication. By reducing the activity of the 3CLpro and PLpro proteases encoded by SARS-CoV-2, biliverdin prevents viral peptides from maturing. The heterodimerization of HO-1 and IRF3 promotes the phosphorylation and nuclear translocation of IRF3, which drives IFN I gene expression. CO: carbon monoxide; 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; PKG, protein kinase G; sGC, soluble guanylate cyclase; RdRp, RNA-dependent RNA polymerase. Figure generated with Biorender (https://biorender.com/accessed on 6 September 2021).