Abstract

Gastric cancer (GC) has poor prognosis and high chemoresistance. This study investigates IKZF3's role in GC progression, oxaliplatin resistance, and underlying mechanisms. IKZF3 expression in GC tissues/cells was assessed using TCGA, qPCR, Western blot, and immunohistochemistry. Prognostic significance was evaluated via Kaplan–Meier analysis. Lentiviral knockdown/overexpression of IKZF3 in HGC27 and AGS cells examined its effects on proliferation, invasion, migration, EMT,tumor stemness and oxaliplatin sensitivity in vitro and in vivo. Additionally, assess whether Iberdomide (an IKZF3 inhibitor) enhances chemosensitivity to oxaliplatin in GC cells in vivo. RNA sequencing (RNA-seq) identified potential mechanisms. PI3K/AKT/mTOR pathway involvement was tested using PI3K inhibitor LY294002 in rescue experiments. IKZF3 was overexpressed in GC (TCGA/tissue microarrays) and correlated with poor prognosis. Knockdown suppressed proliferation, invasion, migration, EMT, tumor stemness and oxaliplatin resistance in HGC27 cells, while overexpression enhanced these in AGS/HGC27 cells. In vivo, IKZF3 knockdown or inhibitor Iberdomide reduced oxaliplatin resistance. RNA-seq indicates that IKZF3 knockdown suppressed PI3K/AKT/mTOR pathway activity in HGC27 cells, while overexpression activated it in AGS cells. LY294002 reversed all oncogenic phenotypes and pathway changes induced by IKZF3 modulation. IKZF3 drives GC progression and oxaliplatin resistance by activating PI3K/AKT/mTOR signaling. It is a potential prognostic biomarker and therapeutic target, supporting further development of LY294002 and Iberdomide for GC treatment. Graphical