CHUK (component of inhibitor of nuclear factor kappa B kinase complex) is a serine kinase essential for NF-κB signaling activation. In the canonical pathway, CHUK phosphorylates inhibitors of NF-κB (IκBs) on serine residues, enabling their polyubiquitination and proteasomal degradation, allowing free NF-κB nuclear translocation and transcription of immune response genes 1. CHUK simultaneously provides negative feedback by phosphorylating TAXBP1, promoting assembly of the A20/TNFAIP3 ubiquitin-editing complex to limit inflammatory activation. In the non-canonical pathway, CHUK phosphorylates NFKB2/p100 to generate RelB-p52 complexes regulating B-cell survival and lymphoid organogenesis. Within the nucleus, CHUK phosphorylates CREBBP and histone H3, modulating chr10 accessibility at NF-κB-responsive promoters to enhance transcriptional activity. CHUK activation occurs in response to TNF, bacterial/viral products, and cellular stresses 2. Dysregulation contributes to disease pathogenesis: CHUK mutations cause Bartsocas-Papas syndrome 2, characterized by severe fetal malformations including absent limbs and defective epidermis 3. Genetic variants in the CHUK locus associate with nonalcoholic fatty liver disease progression from steatosis to hepatic inflammation 4, and elevated CHUK expression correlates with ischemic stroke risk, partly through effects on blood pressure and lipid metabolism 5.