NFKBIZ (NF-kappa-B inhibitor zeta) is a regulatory protein that modulates NF-κB transcription factor activity through dual mechanisms. It inhibits NF-κB DNA-binding activity without affecting nuclear translocation 1, while also activating NF-κB-mediated transcription in association with p50 and p65 subunits 2. NFKBIZ promotes expression of inflammatory mediators including LCN2, DEFB4, and IL-6 2, and participates in TLR/IL-1 receptor signaling pathways and Th17 cell differentiation. In disease contexts, NFKBIZ mutations are frequently selected in inflamed intestinal epithelium of ulcerative colitis patients, where they downregulate pro-inflammatory IL-17 signaling; paradoxically, NFKBIZ-mutant cells are negatively selected during colorectal carcinogenesis 3. NFKBIZ is upregulated in inflammatory conditions including COPD monocyte/macrophages 4, osteoarthritic chondrocytes where it stabilizes in response to ROS 5, and dermal fibroblasts where NFKBIZ-dependent mechanisms promote neutrophil recruitment and host defense against S. aureus 6. Importantly, NFKBIZ expression is posttranscriptionally regulated by regnase-1 and regnase-3, controlling lymphoid-myeloid lineage decisions in hematopoietic stem cells 7. NFKBIZ represents a therapeutic target for inflammatory and degenerative diseases.