IKBKG (also known as NEMO) is the regulatory subunit of the IκB kinase (IKK) complex, functioning as a critical scaffolding protein for NF-κB signaling 1. IKBKG acts as a signaling adaptor that facilitates IKK complex assembly and activation of the catalytic IKK subunits 1. Mechanistically, IKBKG undergoes conformational changes upon binding to linear (M1-linked) polyubiquitin chains, allowing allosteric activation during inflammatory signaling 1. Beyond canonical NF-κB activation, IKBKG mediates recruitment of non-canonical kinases TBK1 and IKKε to TNF receptor complexes, where they phosphorylate RIPK1 to prevent TNF-induced cell death 2. IKBKG also participates in lysosomal homeostasis by recruiting the IKK complex to damaged lysosomes marked by linear ubiquitination, triggering local NF-κB activation and promoting cell survival 3. Alternative splicing of IKBKG regulates autophagy in lung cancer, with specific isoforms influencing disease progression 4. Dysregulation of IKBKG causes severe X-linked disorders: mutations causing loss-of-function result in immunodeficiency syndromes, while mutations causing alternative splicing generate autoinflammatory disease (NDAS), demonstrating isoform-specific pathogenic mechanisms 56. IKBKG variants associate with age-related macular degeneration susceptibility and anti-VEGF treatment response 7.