Scientists at Scripps Research utilized a genome-wide siRNA screening to identify dozens of human host proteins essential for SARS-CoV-2 replication and late infection stages. Their work revealed several known and novel cellular pathways exploited by the virus, including Wnt signaling and NADH oxidation. Two proteins, including the extracellular matrix component perlecan, emerged as promising drug targets. This host-directed antiviral strategy offers broad potential against SARS-CoV-2 variants and future coronavirus threats by mitigating resistance development.