Helicobacter pylori-Induced Persistent IGF2BP1 Activation Promotes Ferroptosis Resistance in Gastric Tumorigenesis

Helicobacter pylori (H. pylori) infection is a major risk factor for gastric cancer, yet how a transient bacterial insult induces durable oncogenic reprogramming in gastric epithelial cells remains incompletely understood. Here, we identify insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) as a key mediator of sustained ferroptosis resistance during gastric tumorigenesis. We show that H. pylori infection induces IGF2BP1 expression in gastric epithelial cells, murine models, and human gastric tissues, and that IGF2BP1 upregulation can persist following bacterial eradication, consistent with a potential "hit-and-run"-like mode of epithelial reprogramming. Functionally, sustained IGF2BP1 expression promotes malignant cell survival and tumor growth by suppressing oxidative stress and ferroptosis. Mechanistically, IGF2BP1 functions as an N⁶-methyladenosine (m⁶A) reader that binds to and stabilizes SLC7A11 mRNA, a key regulator of cystine uptake and redox homeostasis, thereby conferring ferroptosis resistance. Importantly, pharmacological targeting of IGF2BP1 using BTYNB or Cucurbitacin B reduces tumor growth in xenograft models and decreases viability in patient-derived gastric organoids. Together, these findings uncover a mechanism by which infection-triggered epitranscriptomic reprogramming sustains ferroptosis resistance during gastric tumorigenesis and identify IGF2BP1 as a therapeutic target in gastric cancer.