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Target: NFKB1


Research on NFKB1

1. Target Summary:

NFKB1 (Nuclear Factor Kappa B Subunit 1) is a critical transcription factor that plays a pivotal role in regulating immune responses, inflammation, and cell survival. It exists primarily in two forms: p105 (the precursor) and p50 (the processed form). NFKB1 is involved in various biological processes, including the regulation of genes associated with inflammation, apoptosis, and cancer progression. Dysregulation of NFKB1 is implicated in numerous diseases, including cancer, autoimmune disorders, and chronic inflammatory conditions.

2. Mechanism:

NFKB1 functions as a transcription factor that regulates the expression of a wide array of genes involved in immune and inflammatory responses. Under resting conditions, NFKB1 is sequestered in the cytoplasm in an inactive form bound to inhibitory proteins known as IκBs. Upon stimulation by various pro-inflammatory cytokines (e.g., TNF-α, IL-1), IκB proteins are phosphorylated by the IκB kinase (IKK) complex, leading to their ubiquitination and subsequent degradation. This process releases NFKB1, allowing it to translocate into the nucleus, where it binds to specific DNA sequences to activate or repress target gene transcription.
NFKB1 also plays a dual role in inflammation; while it promotes the expression of pro-inflammatory cytokines, it can also induce the expression of anti-inflammatory genes and regulate the resolution of inflammation. For instance, NFKB1 can modulate the expression of microRNAs that target inflammatory pathways, thereby influencing the overall inflammatory response (Cartwright et al., 2016; Concetti & Wilson, 2018).

3. Approved Drugs:

Currently, there are no specific drugs approved solely for targeting NFKB1. However, several compounds that inhibit the NF-kB signaling pathway are being explored in clinical settings. For example, Parthenolide is a known NF-kB inhibitor that has shown promise in reducing tumor growth and inflammation in preclinical studies (Marino et al., 2019).

4. Hypotheses:

  1. Dual Role in Cancer: NFKB1 may act as both a tumor promoter and suppressor depending on the cellular context and the specific dimeric forms it takes (Concetti & Wilson, 2018).
  2. Inflammation Regulation: NFKB1 is hypothesized to play a critical role in the resolution of inflammation, potentially serving as a therapeutic target for chronic inflammatory diseases (Cartwright et al., 2016).
  3. Genetic Polymorphisms: Variants in the NFKB1 gene may influence individual susceptibility to cancer and inflammatory diseases, suggesting that genetic screening could inform personalized treatment strategies (Fu et al., 2017).

5. Validation:

Numerous studies have validated the role of NFKB1 in inflammation and cancer:
  • Animal Models: Nfkb1 knockout mice exhibit increased susceptibility to inflammation and cancer, supporting its role as a tumor suppressor (Cartwright et al., 2016).
  • Clinical Studies: Associations between NFKB1 polymorphisms and cancer risk have been documented, indicating its potential as a biomarker for susceptibility (Li et al., 2017).
  • In Vitro Studies: Inhibition of NFKB1 activity has been shown to reduce the proliferation of cancer cells and modulate inflammatory responses in various cell types (Marino et al., 2019).

6. Clinical Trials:

While specific clinical trials targeting NFKB1 are limited, several trials are investigating the efficacy of NF-kB inhibitors in cancer treatment and inflammatory diseases. For example, trials involving Parthenolide and other NF-kB inhibitors are ongoing to assess their therapeutic potential in various malignancies and inflammatory conditions.

7. Involved Pathways:

NFKB1 is involved in several key signaling pathways, including:
  • NF-kB Signaling Pathway: Central to the regulation of immune and inflammatory responses.
  • Cytokine Signaling Pathways: Such as those activated by TNF-α and IL-1.
  • Apoptosis Pathways: Regulating cell survival and death.

8. Associated Genes:

NFKB1 interacts with numerous genes, including:
  • NFKBIA: The inhibitor of NFKB, which regulates NFKB1 activity.
  • TNF: Tumor necrosis factor, a key pro-inflammatory cytokine.
  • IL-1: Interleukin-1, involved in inflammatory responses.

9. Target Expression:

NFKB1 is expressed in various tissues, with its expression levels often elevated in inflammatory conditions and certain cancers. Studies have shown that tumor specimens frequently exhibit increased NFKB1 expression compared to non-tumor tissues (Song et al., 2025).

10. Additional Context:

NFKB1's role in inflammation and cancer makes it a significant target for therapeutic intervention. Understanding its complex regulatory mechanisms can lead to the development of novel strategies for treating diseases characterized by chronic inflammation and malignancy.

11. References:

  • Cartwright, T., Perkins, N. D., & Wilson, C. L. (2016). NFKB1: a suppressor of inflammation, ageing and cancer. The FEBS Journal, 283(10), 1845-1858. PMID: 26663363
  • Concetti, J., & Wilson, C. L. (2018). NFKB1 and Cancer: Friend or Foe? Cells, 7(9), 138. PMID: 30205516
  • Fu, W., Zhuo, Z. J., & Chen, Y. C. (2017). NFKB1 -94insertion/deletion ATTG polymorphism and cancer risk: Evidence from 50 case-control studies. Oncotarget, 8(9), 15583-15592. PMID: 28039461
  • Marino, S., Bishop, R. T., & Carrasco, G. (2019). Pharmacological Inhibition of NFkappaB Reduces Prostate Cancer Related Osteoclastogenesis In Vitro and Osteolysis Ex Vivo. Calcified Tissue International, 105(2), 195-206. PMID: 30929064
  • Li, D., Wu, C., & Cai, Y. (2017). Association of NFKB1 and NFKBIA gene polymorphisms with susceptibility of gastric cancer. Tumour Biology, 39(7), 1010428317710545. PMID: 28670959
  • Song, Z., Feng, Z., & Wang, X. (2025). NFKB1 as a key player in Tumor biology: from mechanisms to therapeutic implications. Cell Biology and Toxicology. PMID: 39797972
This comprehensive overview of NFKB1 highlights its significance in inflammation and cancer, providing insights into potential therapeutic strategies and future research directions.