Transcriptome analysis identified BAY 11-7082-mediated modulation of host cell responses to SARS-CoV-2 infection
The continued emergence of SARS-CoV-2 variants and persistent inflammatory complications of COVID-19 highlight the urgent need for therapeutics with both antiviral and anti-inflammatory properties. Despite intensive global efforts, no approved antiviral therapy with these dual functions has yet been developed, representing a significant gap in current COVID-19 treatment strategies. In this study, we identify BAY 11-7082 (BAY) as a dual–action compound that inhibits SARS-CoV-2 replication and the production of virus-induced proinflammatory cytokines and chemokines, including IL-6, IL-8, CXCL1, and CXCL2. BAY inhibits SARS-CoV-2 replication at the post-entry stage, significantly reducing viral RNA levels, protein synthesis, and the production of infectious viral particles. Mechanistically, BAY targets SARS-CoV-2 NSP14 and inhibits the subsequent phosphorylation and degradation of I?Ba, effectively suppressing the virus-induced NF-?B activation through the IKK-I?Ba signaling axis. Furthermore, BAY exhibits potent antiviral activity against multiple SARS-CoV-2 variants of concern (VOCs). Collectively, these findings demonstrate that BAY engages the NSP14-driven canonical NF-?B signaling pathway, representing a dual–action therapeutic strategy for COVID-19 while highlighting this pathway as a promising target for broad-spectrum coronavirus interventions.