The transcription factor NF-κB stands as a pivotal regulator of cellular fate, orchestrating an array of physiological and pathological processes. Since its seminal discovery in B lymphocytes by Ranjan Sen and David Baltimore in 1986, NF-κB signaling has become one of the most intensively studied pathways in molecular biology and immunology. Despite nearly four decades of exhaustive research, the intricacy of NF-κB’s signaling networks and its emerging non-canonical roles continue to propel groundbreaking discoveries in this domain, reinforcing its status as a fundamental nexus in immune regulation and disease.
At the forefront of NF-κB research, a collaborative review authored by Professors Alexander Hoffmann and Genhong Cheng from UCLA alongside Nobel laureate David Baltimore from Caltech offers an all-encompassing synthesis of NF-κB’s multifaceted mechanisms and therapeutic potentials. Published in the open-access journal Immunity & Inflammation on September 4, 2025, this authoritative review dissects NF-κB’s canonical and non-canonical activation pathways, the nuanced layers of transcriptional regulation, and the clinical implications of targeting this pathway in diverse diseases.
The canonical NF-κB signaling pathway is predominantly activated by external stimuli such as microbial infection or inflammatory cues. Upon engagement of pattern recognition receptors like Toll-like receptors (TLRs), or cytokine receptors such as TNFR1, and antigen receptors including T cell receptors (TCR) and B cell receptors (BCR), a cascade ensues that culminates in the assembly and activation of the inhibitor of κB kinase (IKK) complex. This complex phosphorylates the inhibitory protein IκBα, marking it for degradation and thereby liberating NF-κB dimers to translocate into the nucleus where they drive transcription of target genes. This pathway is tightly modulated by sophisticated negative feedback loops through proteins like IκB and A20, ensuring balanced immune responses. Dysregulation here can precipitate severe conditions, such as cytokine storms triggered by hyperactive TLR4 signaling or tumorigenesis linked to chronic IKKβ activation.
In juxtaposition, the non-canonical NF-κB pathway unfolds with markedly slower kinetics and principally governs adaptive immune functions including lymphoid organ development and B cell survival. Activated by a limited cohort of tumor necrosis factor receptor superfamily members, this axis hinges on the NF-κB-inducing kinase (NIK) to drive processing of the p100 precursor into p52, shaping a distinct NF-κB dimer composition. The non-canonical route is intricately regulated, with aberrations frequently implicated in malignancies and autoimmune pathologies. Persistent NIK stabilization is a hallmark of several B cell lymphomas, while sustained BAFF signaling prolongs autoreactive B cell lifespan in systemic lupus erythematosus, illustrating the clinical significance of this pathway’s homeostasis.
Importantly, these seemingly discrete signaling routes intersect and engage in molecular cross-talk, with NIK influencing canonical IKK complexes and canonical NF-κB activity inducing expression of components like p100 and A20, creating a highly interconnected regulatory network. This integration ensures that NF-κB responses are finely tuned to cellular context and stimulus type, harmonizing immune activation and developmental processes in a tightly controlled manner.
Transcriptional regulation by NF-κB is exceedingly dynamic and context-specific. The functional outcomes depend heavily on the composition of NF-κB dimers—combinations of RelA, RelB, c-Rel, p50, and p52 subunits—which differ in DNA-binding specificity and interactions with chromatin remodelers and co-regulators. Furthermore, various post-translational modifications on NF-κB subunits provide an additional regulatory dimension, enabling rapid, reversible control of transcriptional activity. This complexity allows NF-κB to exert differential effects on gene expression, sometimes exhibiting opposing functions in inflammation and cell survival, underscoring the pathway’s duality in health and disease.
The pathological spectrum influenced by NF-κB is broad, encompassing chronic inflammatory disorders, oncogenesis, neurodegeneration, metabolic syndromes, cardiovascular diseases, and autoimmunity. Hoffmann and colleagues provide a detailed review of therapeutic modalities targeting NF-κB signaling, ranging from small-molecule inhibitors to biologics that dampen upstream receptor activation or kinase activity. Despite significant progress, these interventions are constrained by side effects such as immunosuppression, development of drug resistance, inadvertent promotion of tumorigenesis, and toxicity. Such challenges highlight the imperative for next-generation strategies with improved precision.
Emerging therapeutic avenues aimed at selectively modulating NF-κB subunits or harnessing novel technologies like proteolysis-targeting chimeras (PROTACs), gene editing tools, nanomedicine delivery systems, and combinatorial immunotherapies represent promising directions for overcoming existing limitations. Tailored approaches that consider the context-dependent nature of NF-κB signaling could revolutionize treatment paradigms in inflammatory and neoplastic diseases by maximizing efficacy while minimizing adverse outcomes.
Looking ahead, the authors emphasize the necessity of integrating cutting-edge technologies including multi-omics analytics, high-resolution imaging, and artificial intelligence-driven data interpretation to dissect NF-κB’s spatiotemporal regulation at molecular and systemic scales. Advancements in these areas will facilitate unprecedented insights into how NF-κB orchestrates complex cellular responses in vivo, paving the way for rational and personalized therapeutic interventions.
Echoing the vision of Professor David Baltimore, who sadly passed away shortly after this publication, the translation of foundational NF-κB research into precision medicine holds promise for tailored combinatorial therapies that address individual patient heterogeneity. This personalized approach aims to harness the full therapeutic potential of NF-κB modulation while mitigating risks, aspiring to transform patient outcomes across a spectrum of immune-related and malignant diseases.
This comprehensive review not only honors the legacy of Prof. Baltimore but sets a new standard in our understanding of NF-κB’s centrality to immunology and beyond. It serves as a critical resource for researchers and clinicians seeking to unravel the intricate biology of this master regulator and to innovate effective therapeutic strategies that can alleviate human suffering caused by NF-κB dysregulation.
Subject of Research: Not applicable
Article Title: NF-κB: Master Regulator of Cellular Responses in Health and Disease
News Publication Date: 4-Sep-2025
References:
DOI: 10.1007/s44466-025-00014-0
Image Credits:
Prof. Alexander Hoffmann and Prof. Genhong Cheng from the University of California, U.S.
Keywords:
Immunology; Signal transduction; NF kappa B pathway; Inflammation; Immune response; Autoimmune disorders; Cancer research; Gene regulation; Drug development
