FGFR signaling and neddylation facilitate SARS-CoV-2 infection by modulating interferon induction and viral entry, respectively.

SARS-CoV-2 is the causative agent of COVID-19, and although vaccines have reduced disease severity, emerging variants remain a significant public health issue. Broadly effective therapeutics, particularly those targeting host pathways essential for coronavirus infection, are still needed. Here, we used a CRISPR knockout screen to identify druggable host factors required for SARS-CoV-2 infection. The screen revealed NAE1 and FGFR1 as key contributors to infection. Inhibitors, either FDA-approved or those in clinical trials, of these pathways reduced replication of both ancestral and contemporary viral variants. Mechanistic studies showed that FGFR1 promotes viral replication through downstream MEK/ERK signaling, while neddylation appears to support viral entry or infectivity rather than replication itself. In a murine model of severe COVID-19, inhibitors of NAE1 and FGFR1 significantly decreased viral load and lung pathology. These findings support the development of host-targeted antiviral strategies.