M6A reader IGF2BP3 stabili1zes SLC7A11 to antagonize ferroptosis and promote gastric tumorigenesis.

The RNA-binding protein IGF2BP3 is implicated in gastric cancer (GC) progression, yet its mechanisms remain incompletely understood. Here, we demonstrate that IGF2BP3 is highly expressed in GC tissues and correlates with poor prognosis. Clinical analyses revealed elevated IGF2BP3 levels in tumors compared to adjacent tissues, with overexpression linked to advanced pathological grading. Functional studies in GC cells showed that IGF2BP3 knockdown suppressed proliferation, migration, invasion, and G1/S cell cycle transition, while its overexpression promoted oncogenic phenotypes. In vivo xenograft experiments confirmed IGF2BP3's tumor-promoting role, with IGF2BP3 knockdown reducing tumor growth and Ki67 expression, whereas overexpression enhanced these parameters. Mechanistically, IGF2BP3 regulated ferroptosis by modulating mitochondrial morphology, intracellular iron accumulation, glutathione depletion, reactive oxygen species (ROS), and lipid peroxidation. Furthermore, IGF2BP3 stabilized SLC7A11 mRNA via N6-methyladenosine (m6A)-dependent mechanisms, as evidenced by reduced mRNA stability upon IGF2BP3 depletion and direct validation of m6A modifications on SLC7A11. Global m6A levels were also influenced by IGF2BP3 expression. Our findings establish IGF2BP3 as a multifaceted oncoprotein driving GC progression through cell cycle dysregulation, ferroptosis suppression, and m6A-mediated SLC7A11 stabilization, providing novel therapeutic targets for GC intervention.