Inhibitor of nuclear factor kappa-B kinase–Nuclear factor kappa-light-chain-enhancer of activated B cells pathway (IKK–NF-κB pathway) (IKK–NF-κB pathway)

The Inhibitor of nuclear factor kappa-B kinase–Nuclear factor kappa-light-chain-enhancer of activated B cells (IKK–NF-κB) pathway is a master regulatory signaling cascade that coordinates the cellular response to inflammatory stimuli, pathogens, and stress (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1074384/). The pathway is primarily controlled by the IKK complex—comprising IKKα, IKKβ, and NEMO—which phosphorylates inhibitory IκB proteins, triggering their ubiquitination and subsequent proteasomal degradation (UniProt, https://www.uniprot.org/uniprotkb/P49327). This process releases NF-κB transcription factor dimers, such as p50/RelA, to translocate into the nucleus and drive the expression of over 100 genes involved in immunity, cell survival, and proliferation (Wikipedia, https://en.wikipedia.org/wiki/NF-%CE%BAB). Dysregulation of this pathway is a hallmark of chronic inflammatory diseases like rheumatoid arthritis and various malignancies, including multiple myeloma and B-cell lymphomas (MDPI, https://www.mdpi.com/2072-6694/14/18/4512). While the pathway is a high-priority therapeutic target, clinical intervention often relies on indirect methods like proteasome inhibition (e.g., bortezomib) or upstream cytokine blockade, as direct IKK inhibitors have faced significant challenges due to severe on-target toxicities such as profound immunosuppression and tissue damage (Guide to Pharmacology, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2039).

Other names

IKK/NF-kappaB signaling pathwayNF-kappaB pathwayIkappaB kinase complexNuclear factor kappa B signaling pathwayIKK-NF-kappaB axis

Inhibition of the IkappaB kinase (IKK) complex to prevent IkappaB phosphorylation, or inhibition of the proteasome to prevent IkappaB degradation, thereby sequestering NF-kappaB in the cytoplasm and preventing its transcriptional activity.