TBK1

TANK-binding kinase 1 (TBK1) is a serine/threonine kinase central to innate immune signaling, mediating phosphorylation of IRF3/7 to induce type I interferon (IFN) and interferon-stimulated genes (ISGs)^[1][2]. Mechanistically, TBK1 participates in antiviral defense via the RIG-I-like receptor (RLR) and TLR pathways, promoting IRF3 nuclear translocation and IFN-β production^[3][4][5]. Alternative splicing generates TBK1 isoforms that can negatively regulate antiviral responses by disrupting TBK1-IRF3 interactions, facilitating proteasomal degradation of TBK1 and lysosomal degradation of IRF3^[3][4][6][5]. TBK1 also supports AKT/mTORC1 pathway activation in cancer, influencing cellular proliferation and survival, with context-dependent effects in KRAS-mutant lung cancers^[7][2]. Dysregulated TBK1 activity is associated with autoimmune diseases, interferonopathies, and cancer, highlighting its therapeutic relevance^[1][8][9]. Pharmacological inhibition using small molecules such as BX795 and amlexanox modulates TBK1-mediated signaling, suppressing inflammation, cellular senescence, and IFN production in disease models, while agonists of downstream effectors like IRF3 can enhance antiviral responses^[10][11][8]. Compared with related kinases, TBK1 demonstrates isoform-specific regulation of IFN signaling and unique interactions with viral or cellular substrates, distinguishing its function from IKKε and other IKK family members^[12][13]. High-throughput assays and computational QSAR models have facilitated the discovery of selective TBK1 inhibitors, providing tools for experimental modulation of innate immune and oncogenic pathways^[12][14]. Collectively, TBK1 acts as a central hub in innate immunity, cancer biology, and inflammatory regulation, with isoform-specific roles and pharmacological manipulability informing research design^[2][15].