H. pylori induces ferroptosis and inhibits malignant progression of gastric epithelial cells via STAT1/SLC7A11 axis

ABSTRACT Helicobacter pylori is a primary risk factor for gastric carcinogenesis; however, an in-depth evaluation of its potential role in modulating ferroptosis to influence cancer development remains undetermined. Therefore, this study developed complementary in vitro cell models (using GES-1 and AGS gastric epithelial cells) and C57BL/6 mouse models to systematically evaluate the mechanism by which H. pylori regulates ferroptosis in gastric epithelial cells. The acquired data revealed that H. pylori infection selectively promotes ferroptotic cell death, which elevates lipid peroxidation, impairs the GPX4-GSH antioxidant axis, and causes intracellular iron overload, resulting in characteristic mitochondrial structural damage. H. pylori disrupts iron homeostasis, alters lipid composition, and impairs redox buffering ability, promoting a ferroptosis-prone microenvironment that mediates epithelial cell death via convergent pathways. Furthermore, H. pylori was found to suppress SLC7A11 expression by two distinct mechanisms: ubiquitin-proteasome-mediated protein destabilization and STAT1-driven transcriptional silencing, which disrupt the antioxidant system and promote ferroptosis. Moreover, pharmacological inhibition of ferroptosis significantly increased the proliferation, motility, and invasiveness of H. pylori -infected gastric cells. These results demonstrate a context-dependent dual role of ferroptosis in H. pylori -mediated gastric tumorigenesis: ferroptosis inhibits tumor growth by eliminating damaged epithelial cells, whereas its inhibition promotes malignant progression. This study reveals a multi-faceted mechanism by which H. pylori mediates ferroptosis, indicating the STAT1/SLC7A11 module as a key regulatory hub, and identifies the dichotomous role of ferroptosis in infection-mediated gastric oncogenesis. These results provide new insights into the pathogenic mechanisms of H. pylori -related gastric cancer and highlight the potential diagnostic and therapeutic targets against the condition. IMPORTANCE Helicobacter pylori infection is a major cause of gastric cancer, but how it regulates gastric epithelial ferroptosis to modulate tumor progression remains incompletely understood. This study explores the underlying mechanisms using cellular and animal models. We show that H. pylori disrupts iron homeostasis and impairs the GPX4-GSH antioxidant system, triggering lipid peroxidation and mitochondrial damage to induce ferroptosis. Mechanistically, H. pylori downregulates SLC7A11 through ubiquitin-proteasome-mediated degradation and STAT1-dependent transcriptional repression. Ferroptosis exhibits a dual role in H. pylori -associated tumorigenesis, suppressing early tumorigenesis while its inhibition promotes malignant progression. This work defines the STAT1/SLC7A11 axis as a key regulatory module and provides novel targets for H. pylori -related gastric cancer.