NKIRAS2 is an atypical Ras-like protein that functions as a potent negative regulator of NF-κB signaling by preventing degradation of the NF-κB inhibitor IκB-β and blocking phosphorylation and nuclear translocation of the p65/RELA subunit 1. Both GTP- and GDP-bound forms of NKIRAS2 suppress NF-κB activity 2. NKIRAS2 exhibits context-dependent roles in cancer. In skin tissues, K15 promoter-driven NKIRAS2 expression suppresses DMBA/TPA-induced tumor development 1. However, NKIRAS2 function displays a biphasic, dose-dependent effect: moderate overexpression enhances HRAS-driven transformation, while excessive expression converts to tumor suppression, suggesting oncogenic activity at specific expression levels 1. Conversely, reduced NKIRAS2 expression is associated with worse prognosis in multiple cancer types without oncogenic RAS mutations 3. NKIRAS2 is frequently targeted by oncogenic microRNAs in cancer. miR-125b, miR-1908-5p, miR-BART13, and miR-4726 directly bind NKIRAS2 3'UTR, suppressing its expression and thereby activating NF-κB signaling to promote proliferation, metastasis, apoptosis resistance, and drug resistance in glioblastoma, osteosarcoma, nasopharyngeal carcinoma, and multiple myeloma, respectively [PMID:24901050; 4; 5; 63]. NKIRAS2 interacts with the pseudoenzyme GFOD1, suggesting additional regulatory mechanisms 2.