Acrylamide-associated gastric cancer progression involves RRM2-related nucleotide metabolic dysregulation and immune...

Acrylamide (AA) is a widespread environmental contaminant and a probable human carcinogen. Its role in gastric cancer (GC), however, remains unclear. We investigated whether AA-associated molecular changes may contribute to GC through altered nucleotide metabolism. Integration of CTD, MSigDB, and GeneCards identified 11 AA-nucleotide metabolism-GC-related genes (ANGRGs). Binding-pocket analysis and non-covalent molecular docking prioritized RRM2 as a candidate associated with AA-related molecular effects. These in silico analyses did not model covalent adduct formation. RRM2 was overexpressed in GC tissues. Functional assays showed that RRM2 promoted proliferation and invasion and reduced apoptosis in GC cells. An RRM2-centered machine-learning model separated patients into distinct risk groups. The high-risk group showed altered nucleotide metabolism and greater predicted resistance to cisplatin and 5-FU. It also showed a computational association with anti-CTLA-4 response, which requires validation in molecularly annotated cohorts. Single-cell analysis showed stronger MIF-, APP-, and CXCL-mediated communication between high-ANGScore tumor cells and immune cells. Drug-response analysis also identified subtype-specific candidate compounds. Together, these findings support an AA-associated, RRM2-related framework linking nucleotide metabolism, malignant behavior, and immune communication in GC. RRM2 is a potential therapeutic target, but the proposed exposure-target relationship requires direct experimental confirmation.