npj Viruses reports a genome-wide host-directed screening strategy that identifies both host-targeted drug candidates and SARS-CoV-2 pro-viral cellular signaling routes. The approach shifts antiviral discovery away from viral proteins alone and instead treats the host genome as the experimental “target space,” capturing dependencies viruses exploit. By mapping cellular pathways that support viral replication, the work creates a set of experimentally grounded leads that can be prioritized for follow-up. For teams working on broad-spectrum antivirals and resistance-resilient targets, the host-pathway angle broadens the targetable surface area beyond conventional direct-acting mechanisms.