IFI16 is a multifunctional innate immune sensor that recognizes pathogenic nucleic acids and regulates inflammatory responses through multiple mechanisms. Primary functions include cytoplasmic double-stranded DNA binding and negative regulation of the AIM2 inflammasome by preventing AIM2-PYCARD/ASC interaction 1. IFI16 acts as a viral RNA sensor that enhances RIG-I transcription and activation during influenza infection, promoting type I interferon production 2. Additionally, IFI16 mediates non-canonical STING activation following nuclear DNA damage through interactions with ATM and PARP-1, triggering NF-κB signaling independent of cGAS 3. In pathological contexts, IFI16 contributes to disease progression and therapeutic resistance. In glioblastoma, IFI16 promotes radioresistance by activating HMOX1 transcription through its pyrin domain interaction with JUND and SP1, thereby suppressing ferroptosis 4. In cervical cancer, IFI16 upregulates PD-L1 expression via the STING-TBK1-NF-κB pathway, enhancing immune evasion 5. During herpesviral infection, lactylation of IFI16 at K90 inhibits DNA-PK recruitment, preventing virus gene repression 6. Conversely, PRMT5-mediated methylation of IFI16 attenuates antitumor immunity in melanoma 7. These findings establish IFI16 as a critical node in innate immunity with dual roles in host defense and disease pathogenesis.