AZI2 (5-azacytidine induced 2) is an adapter protein that plays critical roles in antiviral immunity, cell death prevention, and selective autophagy. Functionally, AZI2 binds TBK1 and IKKε, facilitating TBK1 oligomerization and enhancing phosphorylation of NF-κB p65 subunit RELA to promote NF-κB activation 12. AZI2 participates in type I interferon production via the IFNB promoter through TICAM1-dependent signaling 3. Mechanistically, AZI2 operates through distinct recruitment kinetics in TNF signaling: it is initially recruited via deubiquitinase A20, working alongside TANK adapter to sustain TBK1 activation at the TNF receptor complex, where TBK1 phosphorylates RIPK1 to prevent cell death 4. AZI2 also regulates NDP52-driven mitochondrial autophagy, with its S318 phosphorylation by TBK1 modulating mitophagy efficiency 5. TBK1 sustains AZI2 abundance and phosphorylation state, critical for maintaining autophagy-related protein homeostasis in neurons 6. Clinically, AZI2 positively regulates type I interferon responses in influenza-induced pediatric pneumonia; AZI2-deficient mice show deteriorated pathology and reduced survival 7. In cancer immunotherapy, AZI2-mediated TBK1 activation downstream of autophagy disruption enhances pro-inflammatory chemokine expression and CD8+ T-cell tumor infiltration, offering a sensitization strategy for immunotherapy-resistant breast cancers 8.