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 (IKK) – Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway is a fundamental signaling cascade that coordinates the cellular response to inflammatory stimuli, pathogens, and environmental stress [1, 15]. The pathway is primarily regulated by the IKK complex, which consists of catalytic subunits IKKα and IKKβ and the regulatory subunit NEMO (IKKγ) [2, 17]. Upon activation, IKKβ phosphorylates the inhibitor protein IκBα, marking it for ubiquitination and degradation by the 26S proteasome, which allows NF-κB dimers to translocate into the nucleus [3, 16]. In the nucleus, NF-κB acts as a transcription factor for a wide array of genes involved in the immune response, cell survival, and proliferation [8, 14]. Dysregulation of this pathway, particularly its constitutive activation, is a key driver in chronic inflammatory diseases such as rheumatoid arthritis and various cancers like multiple myeloma and colorectal cancer [11, 13, 19]. Pharmacological intervention strategies include the use of proteasome inhibitors like bortezomib and the development of selective IKK inhibitors, though clinical progress for the latter has been hindered by significant on-target toxicities and the risk of severe immunosuppression [6, 7, 10]. Overall, the IKK-NF-κB axis remains a high-priority target for drug discovery due to its central role in human pathology [1, 21].

Other names

NF-kappaB signaling pathwayIKK/NF-kappaB axisIkappaB kinase complexNF-κB pathwayCanonical NF-κB pathwayNon-canonical NF-κB pathway

Inhibition of IKK-mediated phosphorylation of IκB proteins, prevention of proteasomal degradation of IκB, and blockade of NF-κB nuclear translocation and DNA binding.