Abstract

Background: Despite substantial progress in discovering novel therapeutic targets and compounds, cancer hyperproliferative cells (CHCs) play a central role in driving tumor progression in gastric cancer (GC). High-resolution single-cell RNA sequencing (scRNA-seq) integrated with spatial transcriptomics sequencing (ST-seq) elucidating the role of the CHC microenvironment in driving GC progression remains lacking.

Methods: Through integrated analysis of 40 scRNA-seq samples and 6 ST samples from human gastric tissues spanning tumor progression, we delineate the phenotypic plasticity of tumor epithelium and characterize the transcriptional trajectory from normal gastric cells to CHCs, a process associated with RRM2 overexpression. Finally, we validated the analysis results through cellular and animal experiments.

Results: Our findings demonstrate that RRM2 knockdown triggers ferroptosis in GC cells by promoting lipid peroxidation and intracellular iron accumulation. We further screen a compound and RRM2 inhibitor, osalmid, which effectively suppresses tumor growth in GC cell xenografts by triggering ferroptosis, thus offering a new therapeutic option for GC.

Conclusions: This study elucidates the critical role of RRM2?+?CHCs in gastric cancer development and progression, providing novel insights for targeted therapies. The discovery of osalmid as a potential therapeutic agent offers a promising new treatment strategy for GC.