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

The Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) canonical signaling pathway is a fundamental regulator of the mammalian immune system and inflammatory response (Oeckinghaus & Ghosh, 2009, Cold Spring Harb Perspect Biol). It is activated by a variety of stimuli, including tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and various pathogen-associated molecular patterns (PAMPs) that bind to Toll-like receptors (Liu et al., 2017, Signal Transduct Target Ther). The core of this pathway involves the activation of the IκB kinase (IKK) complex, which phosphorylates the inhibitory protein IκBα, marking it for proteasomal degradation. This degradation releases the NF-κB heterodimer, typically composed of p50 and RelA (p65), allowing it to translocate into the nucleus and initiate the transcription of genes involved in cell survival, proliferation, and the production of pro-inflammatory cytokines (Taniguchi & Karin, 2018, Nat Rev Immunol). Chronic activation of the canonical NF-κB pathway is a hallmark of many inflammatory diseases and cancers, where it contributes to tumor progression and therapeutic resistance (Baud & Karin, 2009, Nat Rev Drug Discov). Therapeutic strategies often focus on inhibiting the IKK complex or the proteasome to prevent NF-κB activation, though such approaches must balance efficacy with the risk of broad immunosuppression (Znatokova et al., 2022, Int J Mol Sci).

Other names

Classical NF-κB pathwayNF-kappaB canonical signalingRelA/p50 signaling pathwayCanonical NF-kappaB pathway

Inhibition of the IκB kinase (IKK) complex, stabilization of the inhibitory protein IκBα through proteasome inhibition, or direct interference with NF-κB nuclear translocation and DNA binding.