SIKE1 (Suppressor of IKBKE 1) functions as a physiological suppressor of IKKε and TBK1 kinases, playing critical inhibitory roles in multiple cellular pathways 1. In innate immunity, SIKE1 inhibits virus- and TLR3-triggered IRF3 activation by disrupting interactions between IKBKE/TBK1 and key signaling proteins including TICAM1/TRIF, IRF3, and RIGI, thereby suppressing interferon-stimulated response elements and IFN-β promoter activation 1. SIKE1 associates with the STRIPAK complex, forming the extended (SIKE1:SLMAP)STRIPAK complex that dephosphorylates STK3, leading to Hippo signaling inhibition and control of cell growth 2. In cardiac physiology, SIKE1 serves as an essential negative regulator of pathological cardiac hypertrophy through direct interaction with TBK1, inhibiting the TBK1-AKT signaling pathway 3. The protein also modulates DNA double-strand break repair and genomic stability, with STRIPAK-mediated MST1/2 inactivation increasing DNA repair capacity and conferring resistance to radio- and chemotherapy 4. SIKE1 expression has prognostic significance in various cancers, with elevated expression generally correlating with unfavorable outcomes in gastric cancer 5. The protein forms homo-oligomeric complexes with a primarily helical structure and exhibits dynamic conformational properties that accommodate interactions with multiple binding partners 6.