IRF2BP1 (interferon regulatory factor 2 binding protein 1) is a nuclear transcriptional corepressor that functions through IRF2-dependent mechanisms independent of histone deacetylase activity. It possesses E3 ubiquitin ligase activity, promoting polyubiquitination of substrates including JDP2, and represses both ATF2-dependent and general RNA polymerase II-mediated transcription 1. Mechanistically, IRF2BP1 operates as a molecular switch in EGFR signaling through transient deSUMOylation, regulating immediate early genes like DUSP1 and ATF3 2. In cancer immunity, IRF2BP1 functions downstream of Cdk5 in the Irf2bp1-Stat1-importin α-Nlrc5 pathway to suppress MHC-I expression, enabling breast cancer brain metastases to evade T cell recognition 3. Clinical significance includes disease associations recently identified through genomic studies. IRF2BP1 variants contribute to neurodevelopmental disorders and microcephaly 4, with protein-truncating variants causing severe immunodeficiency in affected individuals 5. Additionally, IRF2BP1 genetic variants (rs60158447) show significant association with post-ERCP pancreatitis susceptibility 6. IRF2BP1 has also been identified as a fusion partner with RARA in variant acute promyelocytic leukemia 7, and represents a potential therapeutic target for inflammatory bowel disease management 8.