Scripps Research scientists employed comprehensive siRNA screening to delineate human proteins essential for SARS-CoV-2 replication, identifying 59 critical host factors operative at early and late infection stages. Notably, previously unreported pathways like NADH oxidation and arachidonate production were implicated. Two standout targets include the extracellular matrix protein perlecan and cellular pathways modulating viral entry and replication. By focusing on host proteins, this approach potentially circumvents viral mutation-driven resistance, fostering the development of pan-coronavirus therapeutics.