Multi-omics profiling coupled with SHAP analysis and molecular dynamics simulation identifies PIM1 as a therapeutic target in PET-MPs-associated gastric cancer

This study aimed to explore the molecular mechanisms underlying gastric cancer (GC) progression driven by polyethylene terephthalate microplastics (PET-MPs), and screen potential prognostic biomarkers for this specific type of GC. We established an integrated research pipeline combining multiple analytical approaches. Network toxicology analysis, bulk and single-cell RNA sequencing (scRNA-seq) were performed using datasets fromChEMBL/SwissTargetPrediction, TCGA, GSE84437 and GSE163558. Cox regression models combined with SHAP interpretation were constructed for prognostic gene screening. We further conducted molecular docking, 100-ns molecular dynamics (MD) simulations, scTenifoldKnk-based virtual gene knockout, and a series of in vitro functional assays for validation. A total of 17 overlapping genes were identified as potential links between PET-MPs exposure and GC development. Among them, PIM1 (HR = 1.5, P = 0.027) and NOX4 (HR = 1.6, P = 0.009) were identified as independent prognostic risk factors. The constructed Cox model yielded a 5-year AUC of 0.709 in the TCGA cohort, and the corresponding nomogram had a 5-year AUC of 0.701, with favorable predictive performance validated in the GEO cohort ( P = 0.011). Single-cell RNA-seq analysis revealed that both PIM1 and NOX4 were relatively highly expressed in tumor-associated fibroblasts. Virtual knockout via scTenifoldKnk suggested that PIM1 is involved in the regulation of extracellular matrix (ECM) remodeling and cytoskeletal dynamics. Molecular docking results showed that PET-MPs could bind to PIM1 (− 6.4 kcal/mol) and NOX4 (− 6.1 kcal/mol), and MD simulations further supported the stable binding of the PET-MPs-PIM1 complex. In in vitro experiments using HGC-27 cells, PET-MPs notably promoted cell proliferation, migration and invasion ( P < 0.01), and pharmacological inhibition of PIM1 markedly attenuated these malignant phenotypes. PIM1 and NOX4 serve as important molecular mediators in PET-MPs-related GC progression, and show promise as prognostic biomarkers. PIM1 acts as a key functional target, and inhibiting its activity can effectively weaken the oncogenic effects of PET-MPs. This finding provides a potential direction for targeted therapy against PET-MPs-associated gastric cancer.