Preclinical WebsiteClinical Website
Last Updated: September 30, 2025
Authors: Rafael Pérez-Medina-Carballo, M.D., Ph.D., Alexa Brown, Ph.D., and Barry J. Bedell, M.D., Ph.D.

What is the role of NF-κB?

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is defined as a group of proteins that function as transcription factors, playing a crucial role in regulating the expression of genes associated with various cellular functions, including:

The NF-κB transcription factor family includes NF-κB1 (p105/p50), NF-κB2 (p100/p52), RELA (p65), RELB, and c-REL (Barnabei, 2021; Capece, 2022; Guo, 2024). NF-κB plays varying roles depending on the type of immune cell involved (Zinatizadeh, 2021; Anilkumar, 2024; Guo, 2024):

NF-κB signalling pathway

  • In general, NF-κB is bound to an inhibitory protein called IκB (which includes p100, p105, IκBα, and IκBβ) to keep it inactive in the cytoplasm.
  • The I-kappaB kinase (IKK) family activates NF-κB, which then translocates to the nucleus, where it promotes gene expression.

There are two major signalling pathways:

  1. Canonical pathway (Oeckinghaus, 2009; Liu, 2017; Capece, 2022):

    • Activation occurs through pro-inflammatory signals, including cytokines (e.g. TNFα, IL-1β), bacterial and viral products, reactive oxygen species (ROS), and radiation, among others. Key receptors involved include interleukin-1 receptor (IL-1R), toll-like receptors (TLR), TNF receptors (TNFR), T-cell receptors (TCR), and B-cell receptors (BCR).
    • Each signal has a distinct mechanism for activating the IKK complex through different tumor necrosis factor receptor-associated factors (TRAF).
    • Overall, the cascade activates transforming growth factor-β-activated kinase 1 (TAK1), which in turn activates the IKK complex (IKKα and IKKβ) and its related kinase, NEMO (also known as IKKγ).
    • Activated IKK phosphorylates IκB (mainly IκBα) and allows NF-κB translocation into the nucleus.
    • In the nucleus, NF-κB dimers bind to κB DNA sequences that promote gene transcription for:
      • Pro-inflammatory cytokines such as IL-1β, IL-6, and TNFα, to further amplify the inflammatory response.
      • Chemokines to attract other immune cells.
      • Adhesion molecules to attract leukocytes to the inflamed tissue.
      • Other inflammatory mediators such as COX-2 and iNOS.

  2. Non-canonical pathway (Lawrence, 2009; Oeckinghaus, 2009; Liu, 2017):
     
    • The activation of this pathway is slower than the canonical pathway.
    • Specific receptors from the TNF superfamily trigger this pathway, including B lymphocyte activating factor receptor (BAFF-R), CD40, lymphotoxin β receptor (LTβR), and receptor activator of NF-κB (RANK).
    • Activation of these receptors recruits different types of TRAF members to activate NF-κB inducing kinase (NIK).
    • Subsequent activation of NIK leads to phosphorylation of IKKα homodimers.
    • NIK and IKKα phosphorylate p100 (NF-κB2 precursor protein), converting it into the active form known as p52.
    • P52 form the p52/RelB dimer and translocates to the nucleus to promote gene transcription, regulating immune cell survival, communication, development, and maturation of T and B cells.

Since many signalling molecules are activated in both canonical and non-canonical pathways, there is direct and indirect crosstalk with other important signalling pathways, such as PI3K/AKT, MAPK, JAK-STAT, and TGF-β (Guo, 2024).

NF-κB signalling pathways

NF-κB signalling through the canonical and non-canonical pathways.

What are the implications of NF-κB dysregulation in disease?

The role of NF-κB is complex and context-dependent, and it can be considered beneficial or detrimental (Albensi, 2019). While NF-κB is essential for homeostasis, problems in regulating NF-κB are associated with various diseases, including neurological diseases, cancer, inflammatory, and autoimmune diseases.

Neurological Diseases

Under physiological conditions, NF-κB activity in neurons is necessary for normal neuronal function, including neurogenesis, neuritogenesis, and synaptic plasticity (Shih, 2015).

However, dysregulated activation of NF-κB contributes to pathological conditions:

  • Multiple Sclerosis (MS):
    • NF-κB mediates neuroinflammation through infiltrating macrophages, microglia, astrocytes, and peripheral immune cells.
    • NF-κB is also necessary for the transition of T cells into Treg, promoting the pathogenic actions of inflammatory T cells (Guo, 2024).
    • In experimental autoimmune encephalomyelitis (EAE), NF-κB activation triggers neuroinflammation. Interestingly, deleting IKKβ specifically in myeloid cells prevents the induction of EAE, which is associated with a decrease in the production of inflammatory Th1 and Th17 cells (Liu, 2017).

  • Alzheimer’s disease (AD) & Parkinson’s disease (PD):

Cancer

  • NF-κB may promote tumorigenesis primarily through the abnormal activation of the non-canonical pathway. The mechanisms differ for each type of cancer. In general, the mechanisms include the following (Aggarwal, 2011; Xia, 2014):
    • Promotion of cell survival and proliferation: NF-κB contributes to the uncontrolled division of cancer cells by enhancing the expression of cyclins D1 and E, as well as c-Myc, while inhibiting apoptosis through factors such as Bcl-2, Bcl-XL, and IAPs (Brown, 2008; Rinkenbaugh, 2016).
      • For more information about pyroptosis, apoptosis, and necroptosis, refer to the Resource “What is Pyroptosis?”.
    • Promotion of angiogenesis: NF-κB facilitates the formation of new blood vessels through pro-angiogenic factors like VEGF, FGF, PDGF, and IL-8, as well as triggering epithelial-mesenchymal transition, which supports tumor growth and metastasis (Brown, 2008; Park, 2016).
    • Immune evasion: NF-κB contributes to the development of an immunosuppressive tumor microenvironment via TGF-β (Rinkenbaugh, 2016; Guo, 2024).
    • Metabolic reprogramming: NF-κB alters metabolic pathways, leading to increased demand for nitrogen and abnormal mitochondrial oxidative phosphorylation (Guo, 2024).
  • Direct mutations activating NF-κB are common in blood cancers. For instance, c-Rel amplification occurs in non-Hodgkin lymphomas of B-cell origin, and NF-κB2/p100 is frequently activated through chromosomal translocations (Xia, 2014).
  • Abnormal NF-κB regulation has been identified in various cancer types, including squamous cell carcinomas, breast cancer, lung cancer, and colorectal cancer (Brown, 2008).

Autoimmune and Inflammatory Diseases

  • Rheumatoid arthritis (RA): NF-κB perpetuates chronic inflammation and has been found in the synovial fluid of patients with RA. It promotes the production of inflammatory cytokines (IFNγ, IL-15, IL-17, IL-18) in T cells in the joints and the differentiation of bone-resorbing osteoclasts (Liu, 2017; Guo, 2024).
  • Inflammatory bowel disease (IBD): This condition is associated with genetic mutations in NF-κB, which have been identified in diseases such as Crohn’s disease and ulcerative colitis. In patients with IBD, the activation of NF-κB has been observed in their colonic tissues (Liu, 2017).
  • Other autoimmune diseases associated with dysregulation of NF-κB include systemic lupus erythematosus and type 1 diabetes (Guo, 2024).
  • Inflammatory diseases with dysregulation of NF-κB include gout, asthma, acute kidney injury, atherosclerosis, myocardial infarction, and COVID-19 infection (Lawrence, 2009; Liu, 2017).

NEMO Deficiency Syndrome

  • NEMO deficiency syndrome is an X-linked genetic disorder characterized mainly by ectodermal dysplasia and immune deficiency, which increases susceptibility to infections.
  • This condition results from a mutation in the IKBKG gene, which encodes the NEMO protein. The mutation leads to the increased activation of NF-κB (Pescatore, 2022).

What potential therapeutic strategies target NF-κB?

A variety of therapeutic strategies have been developed to target the NF-κB signalling pathway at different points. The dual role of NF-κB, being both anti-tumorigenic and pro-tumorigenic, complicates its therapeutic applications (Xia, 2018).

  • IKK inhibitors (Yu, 2020; Guo, 2024; Li, 2024):
    • Aspirin: An inhibitor of COX and IKKβ, used in animal models for various cancers.
    • Sulfasalazine: An antibiotic that inhibits the expression of TLR4, MyD88, and NF-κB p65 proteins, used in models in vivo to prevent bone metastasis.
    • Dexamethasone: A glucocorticoid that inhibits the RelA subunit of NF-κB.
    • Antitumor drugs: Thalidomide and Lenalidomide inhibit NF-κB activation and show potential in the treatment of lung cancer, leukemia, and multiple myeloma.

  • Monoclonal antibodies (Yu, 2020; Guo, 2024):
    • Anti-PD1/PD-L1: Includes pembrolizumab, atezolizumab, avelumab, durvalumab, and nivolumab.
    • Anti-β2-microglobulin monoclonal antibodies: Aim to reduce NF-κB activity and are under investigation for multiple myeloma.
    • Anti-IL1: Anakinra, Rilonacept, and Canakinumab inhibit the activation of NF-κB via the IL-1R in autoimmune diseases, such as CAPS.
    • Anti-TNFα: Adalimumab, Infliximab, and Etanercept inhibit the activation of NF-κB and are used in different types of cancer.

  • Proteasome inhibitors (Rasmi, 2020; Guo, 2024; Li, 2024):
    • Bortezomib, Carfilzomib, Ixazomib: Inhibit IκBα degradation and suppress NF-κB activity. They are FDA-approved for the treatment of multiple myeloma, diffuse large B-cell lymphoma, and non-small cell lung cancer.

  • Inhibitors of nuclear translocation (Sivamaruthi, 2023; Guo, 2024):
    • Tacrolimus: An immunosuppressive agent. it blocks the activation of the nuclear factor of activated T cells, thereby inhibiting the activation of NF-κB.
    • IκBα super-repressor: Continuous suppression of NF-κB.
    • SN50 peptide inhibits NF-κB by competing with the protein complexes responsible for nuclear translocation.
    • A nanoligomer targeting NF-κB and NLRP3 inflammasome, inhibiting its transcription and translation. This resulted in decreased neuroinflammation and improved cognitive function in AD mouse models (Wahl, 2024).

Some medications not explicitly developed as NF-κB inhibitors have been found to interfere with NF-κB activation (Roberti, 2022):

In MS:

  • Imatinib mesylate: Inhibits various tyrosine kinases and also inhibits IκB phosphorylation, currently undergoing Phase 2 clinical trials for MS (Barnthaler, 2019).
  • Topotecan: Inhibits IKKβ, reducing inflammation in EAE mouse models (Roberti, 2022).

In Alzheimer’s disease:

  • Alogliptin: A hypoglycemic medication that can modulate the TLR4/MyD88/NF-κB pathway in vitro (El-Sahar, 2021).
  • Telmisartan: A medication for high blood pressure that may indirectly reduce NF-κB activity via IL-1β reduction (Sivamaruthi, 2023).

In Stroke:

  • Modafinil: Inhibits NF-κB and provides anti-inflammatory effects, reducing neuronal degeneration in the ischemic hippocampus (Xu, 2024).
  • Atorvastatin: Ameliorates neurological deficits by inhibiting HMGB1-induced NF-κB activation (Xu, 2024).

Targeting the NF-κB signalling pathway thus represents a promising approach for developing therapeutic strategies for various diseases, including neurological diseases, cancer, and autoimmune conditions. A comprehensive understanding of NF-κB's roles is essential for optimizing these strategies and improving treatment outcomes across various disease contexts.

NF-κB signalling pathway

The mechanism of action of NF-κB therapies illustrated through its signalling pathway.

Our team would be happy to answer any questions about Nuclear Factor Kappa B or provide specific information about the neurodegenerative disease models we use for therapeutic efficacy studies.

Discover more about our Neurodegenerative Diseases Models

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