By performing short interfering RNA (siRNA)-mediated candidate gene knockdown and targeting selected proteins with currently available drugs for potential COVID-19 repurposing, we found that RIPK4, SLC7A11, and MASTL were implicated in virus-induced cytotoxicity, which was also validated on two additional variants (Delta and Omicron) that emerged during our study. Here, SLC7A11 is linked to COVID-19.