IRF1 Suppresses Gastric Tumorigenesis via Dual PI3K/AKT-ERK Pathway Modulation and Functional Antagonism of Oncogenic MX2

Background Interferon regulatory factor 1 (IRF1) plays a crucial role in the type I interferon (IFN) response. However, its functional role and underlying mechanisms in gastric cancer (GC) remain unclear. This study aims to investigate the biological significance of IRF1 in GC progression and its potential as a therapeutic target. Methods IRF1 expression was analyzed using The Cancer Genome Atlas (TCGA) and GTEx databases, validated by immunohistochemistry (IHC) in 366 GC patients. Functional experiments, including CCK-8, Transwell migration and invasion assays, and apoptosis analysis, were conducted in GC cell lines with IRF1 overexpression or knockdown. A subcutaneous xenograft model was established to evaluate the in vivo effects of IRF1 on tumor growth. Co-immunoprecipitation and western blotting were performed to explore the molecular interactions between IRF1 and MX2, as well as its regulation of the PI3K signaling pathway. Results IRF1 expression was significantly upregulated in GC tissues compared to adjacent normal tissues and was associated with improved patient survival. Overexpression of IRF1 inhibited GC cell proliferation, migration, and invasion while promoting apoptosis, whereas IRF1 knockdown had the opposite effects. Mechanistically, IRF1 suppressed PI3K/p-AKT signaling while enhancing p-ERK1/2 activation. Moreover, IRF1 directly interacted with MX2, a protein involved in epithelial-mesenchymal transition (EMT), and this interaction was essential for suppressing MX2-mediated oncogenic activity. In vivo experiments confirmed that IRF1 overexpression significantly reduced tumor growth and metastasis. Conclusions IRF1 functions as a tumor suppressor in GC by modulating the PI3K signaling pathway and interacting with MX2 to inhibit EMT. These findings highlight IRF1 as a potential therapeutic target for GC treatment.