IKK

The inhibitor of nuclear factor-κB (IκB) kinase (IKK) complex is a central regulator of the NF-κB signaling pathway, integrating diverse extracellular stimuli to control inflammation and immune responses^[1]. IKKα specifically drives the non-canonical NF-κB pathway by phosphorylating p100, promoting p52/RelB-mediated transcription, whereas IKKβ primarily regulates the canonical pathway through IκBα phosphorylation^[2][3][4]. Mechanistically, IKK activation involves isoform-specific interactions with regulatory proteins such as NEMO and ABIN-2, which selectively enhance IKKα kinase activity and NF-κB transcriptional output^[5][6]. In disease models, IKK dysregulation contributes to inflammatory conditions, cardiomyopathy, retinal epithelial-mesenchymal transition, and cancer, underscoring its therapeutic relevance^[7][8][9]. Compared with IKKβ, IKKα exhibits distinct substrate specificity and differential responses to small-molecule inhibitors, emphasizing the need for isoform-selective pharmacological tools^[10][11][4]. Recent studies have developed potent IKKα-selective inhibitors capable of modulating non-canonical NF-κB signaling in cancer and inflammatory models without affecting IKKβ-dependent pathways^[2][3][4]. These selective compounds enable experimental dissection of IKKα versus IKKβ functions and support rational drug design targeting specific pathological processes mediated by NF-κB^[2][3][4].