Nuclear factor-kappa B signaling pathway (NF-κB)

The Nuclear factor-kappa B (NF-κB) signaling pathway is a ubiquitous and evolutionarily conserved system that regulates the expression of genes involved in inflammation, immune responses, and cell survival (StatPearls, 2023). It comprises five transcription factor subunits—RelA (p65), RelB, c-Rel, p50, and p52—which form various dimeric complexes that bind to specific DNA sequences called κB sites (UniProt, 2024). In most resting cells, NF-κB dimers are kept inactive in the cytoplasm by inhibitory IκB proteins; however, stimuli such as pro-inflammatory cytokines (e.g., TNF-α, IL-1) or pathogen-associated molecular patterns (PAMPs) trigger the IκB kinase (IKK) complex to phosphorylate IκB, leading to its proteasomal degradation (Nature Reviews Drug Discovery, 2012). This release allows NF-κB to translocate to the nucleus and activate the transcription of over 500 genes, including those for cytokines, chemokines, and anti-apoptotic proteins (PubMed, 2017). Aberrant NF-κB activation is strongly linked to the pathogenesis of chronic inflammatory conditions like rheumatoid arthritis and various malignancies, where it drives tumor proliferation and chemoresistance (NIH, 2018). Therapeutic strategies targeting this pathway include proteasome inhibitors like Bortezomib, which prevent IκB degradation, and various experimental small molecules designed to inhibit IKK activity (PubChem, 2024).

Other names

NF-kappaBNFKBRel signaling pathwayIKK/NF-kappaB pathwayNuclear factor kappa-light-chain-enhancer of activated B cells pathway

Inhibition of the IκB kinase (IKK) complex, inhibition of the 26S proteasome to prevent IκB degradation, and direct interference with NF-κB DNA binding or nuclear translocation.