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 N ⁶ ‐methyladenosine (m ⁶ A) 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.

Background: Ovarian cancer (OC) remains the most lethal gynaecological malignancy, and acquired resistance to PARP inhibitors such as olaparib represents a major clinical challenge. Although dysregulation of iron metabolism has been implicated in tumorigenesis, the specific role of the iron exporter SLC40A1 (ferroportin, FPN) in mediating olaparib resistance remains poorly understood. The study aimed to elucidate the clinical significance of FPN deficiency and to explore therapeutic strategies for reversing olaparib resistance. Methods: FPN expression was evaluated in OC samples from a clinical cohort of 19 patients, stratified by olaparib responsiveness, to determine its prognostic value. Functional mechanisms were investigated using multiple OC cell lines, patient‐derived organoids (PDOs), and mouse xenograft models. We integrated analyses of iron homeostasis, ROS dynamics, DNA repair capacity, and innate immune signaling, with a focus on the cGAS–STING–STAT3 signaling cascade. The therapeutic potential of combining olaparib with the ferroptosis inducer erastin or the STING inhibitor C‐176 was assessed as a strategy to overcome FPN deficiency‐driven resistance. Results: Clinically, FPN expression was significantly downregulated in olaparib‐resistant tissues compared with sensitive controls ( p < 0.05), and low FPN levels were strongly associated with poor therapeutic outcomes. Mechanistically, FPN deficiency promoted intracellular iron accumulation and ROS generation, which led to increased ferroptosis vulnerability, impaired homologous recombination repair (HRR) and concomitant activation of the cGAS–STING–STAT3 inflammatory axis, thereby driving olaparib resistance. Notably, in vivo studies demonstrated that combining olaparib with either erastin or C‐176 significantly suppressed tumour growth and restored drug sensitivity compared with monotherapy ( p < 0.01), supporting the translational potential of targeting this axis. Conclusions: Our study establishes a clinically relevant mechanistic connection between ferroportin deficiency and cGAS–STING–STAT3‐mediated olaparib resistance in OC. We identify the FPN–ROS–cGAS–STING–STAT3 axis as an actionable vulnerability in resistant OC, indicating that this pathway is a promising therapeutic target to overcome olaparib resistance. Highlights: FPN loss drives olaparib resistance and predicts poor outcomes in ovarian cancer. FPN loss causes iron and ROS accumulation, impairing HRR and activating the cGAS–STING–STAT3 axis. The cGAS–STING–STAT3 pro‐survival program drives olaparib resistance. STING inhibition restores olaparib sensitivity in resistant ovarian cancer.

KRAS inhibitors represent a promising therapeutic frontier in pancreatic ductal adenocarcinoma (PDAC) treatment. However, the clinical benefit of KRAS inhibitors in PDAC is limited by the frequent emergence of resistance. Here, we demonstrated that acquisition of resistance to KRAS inhibitors rendered PDAC cells hypersensitive to ferroptosis. Untargeted lipidomic profiling revealed that resistant cells underwent extensive lipid metabolic reprogramming characterized by selective enrichment of polyunsaturated fatty acid–containing phosphatidylcholines (PC-PUFAs) and a concomitant reduction in monounsaturated fatty acid–containing species (PC-MUFAs). The orphan nuclear receptor NR2F2 was a critical determinant of ferroptosis sensitivity in resistant cells. NR2F2 expression was markedly elevated upon acquisition of resistance, accompanied by substantial changes in its occupancy at regulatory elements of key lipid metabolic genes. By altering chromatin accessibility, NR2F2 drove PUFA biosynthesis and phospholipid remodeling, creating a ferroptosis-prone lipid state. Collectively, these findings establish NR2F2-driven lipid metabolic rewiring as an intrinsic ferroptosis liability in KRAS inhibitor–resistant PDAC and reveal ferroptosis induction as a therapeutic strategy to overcome resistance to KRAS-targeted therapies.