Nuclear factor kappa-light-chain-enhancer of activated B cells pathway (NF-κB pathway) (NF-κB pathway)

The Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway is a master regulatory system that controls the transcription of genes essential for innate and adaptive immunity, inflammation, and cell survival [1.1.1, 1.1.4]. The pathway comprises a family of five transcription factor subunits—p50, p52, RelA (p65), RelB, and c-Rel—which form various homo- and heterodimers [1.1.2, 1.3.4]. In resting cells, these dimers are kept inactive in the cytoplasm by inhibitory IκB proteins [1.1.1, 1.2.5]. Activation occurs when upstream signals, such as cytokines or pathogen-associated molecular patterns, trigger the IκB kinase (IKK) complex to phosphorylate IκB, leading to its proteasomal degradation and the subsequent nuclear translocation of NF-κB [1.1.1, 1.4.2]. Aberrant or constitutive activation of this pathway is strongly linked to the pathogenesis of various cancers, autoimmune disorders, and chronic inflammatory conditions [1.1.4, 1.2.4]. Therapeutic interventions target this pathway through several mechanisms, including proteasome inhibition (e.g., bortezomib) and the development of specific IKK or NIK inhibitors [1.2.1, 1.3.3]. Despite its therapeutic potential, systemic blockade of NF-κB is associated with significant safety concerns, primarily severe immunosuppression and on-target toxicities, due to its ubiquitous role in maintaining cellular homeostasis [1.2.4, 1.5.1].

Other names

NF-kappaB signalingNF-kB pathwayIKK complexRel/NF-κB proteinsCanonical NF-κB pathwayNon-canonical NF-κB pathway

Inhibition of the proteasome to prevent IκB degradation, inhibition of IKK complex kinases to block phosphorylation of inhibitors, or neutralization of upstream activating ligands such as TNF-α and RANKL.