Increasing autophagy activity suppresses Helicobacter pylori infection-related gastric cancer tumorigenesis both in vitro and in vivo.

Helicobacter pylori (H. pylori) infection is a major risk factor for gastric cancer (GC). Although autophagy is involved in H. pylori infection, its role in H. pylori-associated tumorigenesis remains unclear. Here, we investigated whether enhancing autophagy suppresses GC malignancy under H. pylori infection. Autophagy and mitochondrial markers were analyzed in GC tissue microarrays and the TCGA-STAD dataset. Functional studies employed H. pylori (strain 49503)-infected GC cell lines and xenograft models, with autophagy manipulated by pharmacological induction, Atg5 knockout, gene silencing, or overexpression. Molecular and cellular analyses included Western blotting, luciferase reporter assays, RNA sequencing, transmission electron microscopy (TEM), mitochondrial function tests, and additional functional assays. We observed elevated levels of LC3 and p-Drp1 in tumor tissues. H. pylori infection increased autophagy, cell migration, sphere formation, and transient tumor growth, while reducing cell viability and colony formation; autophagy induction suppressed these malignant features. TEM revealed abundant autophagy-like vesicles and mitochondrial alterations in infected cells. Mechanistically, H. pylori activated the Erk1/2 and JNK signaling pathways to induce autophagy while inhibiting other oncogenic signaling pathways. Notably, although H. pylori induces robust autophagy, further enhancement of this process using autophagy inducers attenuated gastric cancer malignancy, suggesting that further pharmacological modulation of autophagy warrants evaluation as a potential therapeutic strategy.