Unveiling the multifaceted roles of BCL3: biological functions and disease implications

BCL3 (B-cell CLL/lymphoma 3), initially identified in the t(14;19) chromosomal translocation in B-cell malignancies, is an atypical member of the inhibitor of NF-κB (IκB) protein family. Unlike classical IκB proteins, BCL3 predominantly localizes to the nucleus, where it exerts unique bidirectional transcriptional regulatory functions within the NF-κB signaling pathway. This complex functionality is finely modulated by post-translational modifications, particularly phosphorylation. Under pathological conditions, BCL3 functions as an oncogene, driving abnormal neoplastic cell proliferation, inhibiting apoptosis, and promoting metastasis and chemotherapy resistance in various hematological malignancies and solid neoplasms by activating multiple oncogenic signaling pathways. Conversely, BCL3 also serves as a critical regulatory factor of immune homeostasis, modulating the functions of macrophages, T cells, and dendritic cells (DCs), thereby influencing the pathogenesis of immune-related disorders. Beyond oncology and immunology, BCL3 plays pivotal roles in the nervous, cardiovascular, digestive, and musculoskeletal systems, highlighting its broad physiological and pathological significance. This article systematically reviews the molecular structure, post-translational regulatory mechanisms, and multifaceted roles of BCL3 in neoplastic and non-neoplastic diseases. By consolidating current research, this review aims to provide novel insights into the diagnostic and therapeutic potential of targeting BCL3 in related pathologies.