NFX1 (nuclear transcription factor, X-box binding 1) is a zinc finger transcription factor that functions as both a transcriptional repressor and coactivator with isoform-specific roles. NFX1 binds X-box motifs to repress MHC class II gene expression, potentially limiting inflammatory responses 1. The protein contains RING finger domains with E3 ubiquitin ligase activity, mediating protein ubiquitination and degradation 2. NFX1 exhibits complex regulation of telomerase: isoform 3 represses TERT expression, while isoform 1 acts as a coactivator with PABPC1/PABPC4 1. The longer splice variant NFX1-123 is notably elevated in HPV-associated cancers, where it collaborates with HPV16 E6 to downregulate innate immune genes and interferon-stimulated genes, promoting immune evasion 3. NFX1-123 and E6 also increase Notch1 expression and differentiation without triggering growth arrest, uncoupling differentiation from senescence 4. Recently, lysosomal degradation of NFX1 was identified as a mechanism facilitating tumor immune escape through galectin-9 induction 5. In antiviral immunity, the NFX1-family member ZNFX1 acts as a double-stranded RNA sensor critical for interferon responses 6. Collectively, NFX1 regulates inflammatory, immune, and cancer-related pathways through transcriptional and post-translational mechanisms.