The transcription factor NF-κB is a key regulator of cell fate, extensively involved in various physiological and pathological processes such as immune responses, inflammatory reactions, cell differentiation, development, and proliferation. Since its transcriptional regulatory function was first identified in B cells by Ranjan Sen and David Baltimore in 1986, the NF-κB signaling pathway has been intensively studied for almost four decades. However, its complex regulatory network and continuously discovered non-canonical biological functions continue to bring new breakthroughs to this field. To date, research into the functions and mechanisms of NF-κB continues to be a leading frontier in immunology and the life sciences.
In a recently published review article, Professor Alexander Hoffmann and Genhong Cheng from the University of California, Los Angeles, along with Professor David Baltimore from the California Institute of Technology, aimed to comprehensively summarize the diverse roles, mechanisms, and therapeutic targeting of NF-κB in immune regulation, inflammation, and disease. Their article was published online in the journal Immunity & Inflammation on September 04, 2025.
NF-κB activation primarily occurs through two pathways: the canonical and non-canonical routes. The canonical pathway is typically triggered by exogenous signals such as infection or inflammation, involving the activation of Toll-like receptors (TLRs), cytokine receptors (e.g., TNFR1), and antigen receptors (TCR/BCR). These receptors recruit specific adapter proteins, subsequently activating the IKK complex, leading to IκBα degradation and the release of NF-κB into the nucleus to initiate downstream gene transcription. This pathway is precisely regulated by multiple layers of negative feedback mechanisms, and its dysregulation is closely associated with various diseases. Examples include cytokine storms and systemic inflammation caused by excessive TLR4 activation during bacterial infections, or tumorigenesis resulting from persistent IKKβ activation in the intestinal epithelium in chronic enteritis.
The non-canonical pathway is activated by specific members of the tumor necrosis factor receptor superfamily (TNFRSF). It exhibits slower kinetics and is primarily involved in regulating lymphoid organogenesis, B cell survival, and the expression of genes related to adaptive immunity. This pathway is specifically regulated by factors such as NIK, and its aberrant activation is commonly observed in tumors and autoimmune diseases. For instance, persistent accumulation of NIK has been seen in B cell malignancies, and chronic BAFF signaling prolongs the survival of autoreactive B cells in systemic lupus erythematosus (SLE).
"Notably, the canonical and non-canonical pathways intersect at the molecular level, cooperatively regulating key life processes such as immune responses and cell development," explains Prof. Cheng.
NF-κB-mediated transcriptional regulation is highly dynamic and context-dependent. The article details its regulatory mechanisms, including the composition of NF-κB dimers, the binding specificity of dimers to enhancer elements, and interactions with co-regulators and chromatin remodeling complexes. Additionally, post-translational modifications provide a rapid and reversible means of regulating NF-κB activity, further enhancing its flexibility in responding to external signals. Different dimers can have distinct or even opposing effects on gene expression, highlighting the extreme complexity of this signaling network. Understanding these mechanisms is crucial for elucidating the role of NF-κB in physiology and pathology, and for developing precise targeted therapeutic strategies.
"Our article also systematically elaborates on the central role of NF-κB in various diseases, including inflammatory diseases, tumors, neurodegenerative diseases, metabolic and cardiovascular diseases, and autoimmune diseases," remarks Prof. Hoffmann. It comprehensively reviews therapeutic drugs targeting the NF-κB signaling pathway, their mechanisms of action, and clinical progress. However, existing drugs still face limitations such as compromised host defense mechanisms, treatment resistance, potential tumor-promoting risks, and toxic side effects. In response to these challenges, emerging therapeutic strategies are continuously being developed, including subunit-specific targeting, proteolysis-targeting chimeras (PROTACs), gene editing, nanomedicine, and immunotherapy combination, offering new directions for intervening in NF-κB signaling.
Finally, the authors look ahead to future development trends in NF-κB research, pointing out the need to integrate multi-omics technologies, high-resolution imaging and artificial intelligence to analyze the spatiotemporal transcriptional regulatory functions of NF-κB at both the molecular and the systematic levels. And Prof. Baltimore further emphasizes "the importance of translating these basic research findings into precision medicine to ultimately develop personalized, combinatorial treatment plans for patients".
This is the final scientific article of Prof. David Baltimore. We were deeply saddened by his passing on September 6, 2025 and we wish to honor his immense contributions to science.
