PLSCR2 (phospholipid scramblase 2) is a membrane-associated protein located on chromosome 3 that lacks functional phospholipid scramblase activity due to the absence of an N-terminal proline-rich domain [UniProt]. Its primary function is to suppress type I interferon (IFN-I) responses through interaction with STAT3. PLSCR2 binds to the N-terminal domain of STAT3 in a palmitoylation-dependent manner and cooperatively suppresses IFN-I-induced gene expression by impeding ISGF3 complex promoter occupancy 1. PLSCR2 deficiency enhances IFN-I-induced antiviral activity and gene expression without affecting STAT1/STAT2 activation or ISGF3 assembly, indicating that PLSCR2 specifically blocks downstream transcriptional events 1. Additionally, PLSCR2 interacts with STAT2, further intensifying suppression of ISGF3-mediated transcription 1. Beyond innate immunity, PLSCR2 expression is dysregulated in disease contexts: differential methylation of PLSCR2 is associated with prostate cancer progression in African American populations 2, and altered PLSCR2 methylation correlates with left ventricular hypertrophy severity in hypertrophic cardiomyopathy patients 3. PLSCR2 protein expression is downregulated in breast cancer cells following ionizing radiation exposure 4. These findings establish PLSCR2 as a key negative regulator of antiviral immunity with emerging roles in cardiac and malignant disease pathogenesis.