PLSCR1 (phospholipid scramblase 1) is an interferon-stimulated gene that functions as a broad-spectrum cell-autonomous antiviral restriction factor. Primary function: PLSCR1 restricts viral entry across multiple pathogens, including SARS-CoV-2, HIV-1/2, SIV, and human cytomegalovirus (HCMV) 123. Mechanism: PLSCR1 employs pathogen-specific mechanisms depending on the virus. Against SARS-CoV-2, it blocks spike-mediated fusion via a C-terminal β-barrel domain independent of lipid scramblase activity 1, and separately downregulates plasma membrane expression of ACE2 without reducing total cellular ACE2 levels 2. For HIV-1, PLSCR1 restricts virion-cell and cell-cell fusion without affecting CD4 or CXCR4 expression 3. Against HCMV, it represses viral immediate early gene transcription by disrupting CREB-IE2 and CBP-IE2 complexes 4. Disease relevance: Genetic variants in PLSCR1 are associated with critical COVID-19 severity 5, and PLSCR1 mutations have been identified in COVID-19 susceptible individuals 1. PLSCR1 is upregulated in systemic lupus erythematosus and correlates with interferon signature activity 6. Clinical significance: PLSCR1 activity extends to multiple SARS-CoV-2 variants including Delta and Omicron 1, though recent variants show evidence of evolutionary adaptation to circumvent PLSCR1 restriction 7.