IKBKE (inhibitor of nuclear factor kappa B kinase subunit epsilon) is a serine/threonine kinase that functions as a critical regulator of innate immune responses to viral infection. Following viral RNA sensor activation, IKBKE phosphorylates interferon regulatory factors IRF3 and IRF7, promoting their nuclear translocation and transcriptional activation of type I interferon and antiviral genes [UniProt]. It also phosphorylates STAT1 to regulate interferon-stimulated gene expression and coordinates balanced type I/II interferon responses [UniProt]. Additionally, IKBKE phosphorylates TAX1BP1 to regulate selective autophagy of MAVS aggregates, preventing excessive inflammatory signaling 1. Beyond antiviral immunity, IKBKE activates NF-κB signaling through CYLD phosphorylation and plays roles in TNF and interleukin-1 responses [UniProt]. Clinically, IKBKE variants associate with increased systemic lupus erythematosus (SLE) susceptibility, with functional variants affecting splicing factor binding and transcriptional regulation 23. Notably, IKBKE is upregulated in renal cell carcinoma, correlating with advanced staging and poor prognosis; IKBKE inhibition suppresses cancer progression and restores sunitinib sensitivity through the RRM2-AKT pathway 4. IKBKE polymorphisms also associate with major depressive disorder and panic disorder, suggesting involvement in mood and anxiety disorders 5. These findings position IKBKE as a potential therapeutic target across inflammatory, autoimmune, oncologic, and psychiatric diseases.