Helicobacter pylori induced STAT1-K193 lactylation drives gastric cancer progression

Helicobacter pylori ( H. pylori ) infection is a major risk factor for gastric cancer (GC). Lactylation, a recently identified lactate-driven post-translational modification, plays a key role in gene transcription regulation. It is closely linked to glycolysis and the Warburg effect. However, the role of non-histone lactylation in bacteria-induced tumorigenesis remains poorly understood. Untargeted serum metabolomics of 331 patients with H. pylori -associated gastritis and gastric cancer (GC) was performed to evaluate systemic metabolic alterations. Immunohistochemistry, global lactylation proteomics, in vitro assays (using MGC803 human and MFC mouse GC cell lines), and in vivo assays were conducted. CRISPR/Cas9 gene editing, overexpression systems, and pharmacological approaches investigated STAT1-K193 lactylation. Glycolytic flux assays assessed metabolic consequences, and single-cell RNA sequencing of subcutaneous tumors derived from STAT1-WT or STAT1-K193R MFC cells in immunocompetent C57BL/6J mice characterized tumor immune microenvironment alterations. H. pylori infection significantly activates glycolysis, increasing L-lactate production and global intracellular L-lactylation, with marked elevation at lysine 193 (K193) of STAT1. Functionally, STAT1-K193 lactylation (STAT1-K193la) promotes the proliferation and migration of MGC803 and MFC GC cells in vitro and drives tumor progression in vivo. Mechanistically, the lactyltransferase p300 regulates STAT1-K193la levels, which in turn binds to and transcriptionally activates ISG15, forming a positive feedback loop that enhances glycolysis in H. pylori -exposed GC cells. Furthermore, single-cell RNA sequencing demonstrates that loss of STAT1-K193la impairs the immunosuppressive tumor microenvironment and increases the proportion of effector immune cells, such as CD8 + T cells. These findings uncover a regulatory role for STAT1-K193 lactylation in H. pylori -induced GC progression, pointing to metabolic-driven protein modifications as a relevant axis in gastric carcinogenesis.