AZI2 is an adapter protein that functions as a critical regulator of antiviral innate immunity and cell survival signaling. It binds TBK1 and IKKε kinases, activating TBK1 and facilitating its oligomerization 1, while enhancing phosphorylation of the NF-κB p65 subunit and promoting NF-κB-dependent gene activation 1. AZI2 participates in type I interferon production via TBK1 activation, particularly during viral infection; in influenza-induced pediatric pneumonia, AZI2 deficiency impaired type I interferon responses and worsened pathological outcomes 2. Beyond antiviral defense, AZI2 protects cells from TNF-induced cell death by recruiting TBK1 to the TNF receptor signaling complex, where it phosphorylates RIPK1 to prevent RIPK1-dependent death 3. Mice deficient in both AZI2 and TANK adapters develop severe multi-organ inflammation, autoimmunity, and early mortality—phenotypes rescued by TNFR1 deficiency, demonstrating AZI2's role in suppressing autoinflammatory disease 4. Recent evidence suggests AZI2 also regulates mitochondrial autophagy through cooperation with NDP52 and TBK1 5, and can be therapeutically targeted to enhance anti-tumor immunity; blocking selective autophagy activators like Lys05 accumulate AZI2 at autophagic cargo receptor complexes, activating TBK1-driven interferon signaling and CD8+ T-cell infiltration in breast cancer 6.