BCL3 is a transcriptional coactivator that plays dual regulatory roles in NF-κB signaling and cellular responses. In the cytoplasm, BCL3 inhibits nuclear translocation of NF-κB p50, while in the nucleus it acts as a transcriptional activator promoting NF-κB target gene expression 1. BCL3 regulates pro-survival genes including cIAP1 and cIAP2 through direct promoter binding, and its expression is controlled by proteasome inhibition and NF-κB subunit exchange on its own promoter 1. In disease contexts, BCL3 shows opposing roles. In allergic asthma, BCL3 prevents allergic sensitization by suppressing B-cell-derived IL-10 production under Bcl-3-Blimp-1-Bcl-6 regulation; BCL3 knockout mice show heightened vulnerability to house dust mite-induced asthma 2. Conversely, in pancreatic cancer, BCL3 acts as a tumor suppressor—BCL3 loss expands the cancer stem cell compartment, increases epithelial-mesenchymal transition, promotes metastasis, and reduces overall survival, while BCL3 expression levels stratify patients by molecular subtype and prognosis 3. In systemic lupus erythematosus, BCL3 expression is dysregulated downstream of IRF4 in plasma cells, contributing to kidney injury through TNF signaling pathway activation 4. BCL3 is also implicated in cutaneous T-cell lymphoma pathogenesis 1 and identified as a biomarker for secondary progressive multiple sclerosis 5. Additionally, BCL3 polymorphisms associate with dyslipidemia risk through gene-gene and gene-environment interactions 6.