NFKBIL1 (NF-κB inhibitor like 1) is an immune regulatory protein encoded within the HLA locus on chromosome 6 that functions as a negative regulator of innate immune signaling. The protein suppresses Toll-like receptor and interferon-regulatory factor pathways, thereby limiting NF-κB-dependent transcriptional activation of pro-inflammatory genes 1. Beyond canonical NF-κB inhibition, NFKBIL1 regulates alternative splicing of immune-related genes such as CD45 through interaction with the kinase CLK1 and SR proteins, independent of CLK1's catalytic activity 1. This splicing function extends to viral genes, including influenza M gene variants 1. NFKBIL1 modulates dendritic cell function by reducing co-stimulatory molecule expression and inflammatory cytokine production, thereby limiting T cell activation 2. Transgenic mice expressing human NFKBIL1 demonstrate resistance to experimental autoimmune arthritis 2. Genetic variants in NFKBIL1 associate with susceptibility to multiple conditions including rheumatoid arthritis, psoriasis, and potentially autism spectrum disorder-related traits 34. However, NFKBIL1 polymorphisms show protective effects against myocardial infarction in European populations 5, suggesting context-dependent or population-specific disease associations.