PTTG1 drives intestinal-type gastric cancer progression via G2/M checkpoint-mediated cell-cycle reprogramming.

Intestinal-type gastric cancer (IGC) progresses through the Correa cascade, yet the molecular determinants of this transition remain insufficiently defined. Using single-cell RNA sequencing (scRNA-seq) on matched normal, intestinal metaplasia, and tumor tissues from five patients, we identified eight epithelial subtypes, including a transitional enterocyte population that expanded along the disease trajectory. Pseudotime and network analyses revealed a progressive upregulation of PTTG1, which was further supported by public cohorts, bulk transcriptomics, and tissue microarrays. Functional assays demonstrated that PTTG1 knockdown impaired G2/M checkpoint regulation and reduced gastric cancer cell proliferation, migration, and invasion, whereas its overexpression enhanced organoid growth and altered mucin-related features. In xenograft models, PTTG1 depletion suppressed tumor growth and was accompanied by secretory differentiation-associated histological changes. Collectively, these findings suggest that PTTG1 contributes to intestinal-type gastric cancer progression by regulating G2/M checkpoint-associated programs and modulating mucin-associated phenotypes, supporting its potential as a risk biomarker and candidate therapeutic target for IGC prevention.