IKBKB (inhibitor of nuclear factor kappa B kinase subunit beta) is a serine kinase that serves as a critical component of the canonical IKK complex, functioning as a central regulator of NF-κB signaling 1. The protein phosphorylates inhibitors of NF-κB at two critical serine residues, enabling their polyubiquitination and proteasomal degradation, thereby liberating NF-κB for nuclear translocation and transcriptional activation of genes controlling immune response, growth, and apoptosis suppression 2. Beyond classical substrates, IKBKB phosphorylates multiple signaling pathway components including NEMO/IKBKG, NF-κB subunits RELA and NFKB1, and IKK-related kinases TBK1 and IKBKE, with the latter phosphorylations exerting negative regulation to prevent inflammatory overproduction. The kinase also regulates non-canonical substrates including FOXO3, RIPK1, IRF5, and STAT1, the latter controlling interferon signaling and IL6/IL12B transcription. Recent evidence reveals IKBKB regulates metabolism and tumorigenesis through the USP30-ACLY axis in hepatocellular carcinoma 3 and promotes compensatory glucose uptake in brain tumors via α-ketoglutarate-activated NF-κB signaling 4. Clinically, biallelic loss-of-function IKBKB variants cause severe combined immunodeficiency, while heterozygous gain-of-function variants associate with autoimmunity and autoinflammation 5. IKBKB polymorphisms also influence age-related macular degeneration susceptibility and anti-VEGF treatment response 6.