Helicobacter pylori Gpt targets SLC7A11 to trigger ferroptosis and promote chronic atrophic gastritis
摘要
Helicobacter pylori (H. pylori) infection is a major driver of gastric diseases, but with a global prevalence of nearly 50%, precise risk stratification among infected individuals remains challenging. Here, we constructed a comprehensive H. pylori proteome microarray encompassing 1,631 proteins and applied it to screen sera from patients with chronic atrophic gastritis (CAG), providing a practical entry point to dissect virulence-host interactions that shape disease progression. Through systematic screening, we identified glutamate pyruvate transaminase (Gpt) as a CAG-associated antigen. In independent validation cohorts, anti-Gpt IgG demonstrated high accuracy in distinguishing patients with CAG from those with chronic non-atrophic gastritis among H. pylori-infected individuals. Mechanistically, Gpt binds to the cystine/glutamate antiporter subunit SLC7A11 with nanomolar affinity (KD = 14.8 nM), destabilizing the SLC7A11-SLC3A2 heterodimer and thereby impairing cystine uptake. Consequently, Gpt reduces the antioxidant capacity of gastric epithelial cells by depleting glutathione, downregulating GPX4, and increasing lipid peroxidation, ultimately triggering ferroptosis. This ferroptotic phenotype is reversed by the ferroptosis inhibitor liproxstatin-1 and is markedly reduced during infection with a gpt-deficient H. pylori strain. Finally, in gastric biopsy samples from patients with CAG, Gpt expression spatially coincides with malondialdehyde accumulation, supporting in vivo activation of ferroptosis. These findings identify Gpt as a previously unrecognized H. pylori virulence factor that promotes CAG through ferroptosis, and they highlight anti-Gpt IgG as a promising noninvasive biomarker for risk stratification in H. pylori infection, enabling the identification of individuals at higher risk of progressing to precancerous gastric lesions.
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