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Multi-omics profiling coupled with SHAP analysis and molecular dynamics simulation identifies PIM1 as a therapeutic target in PET-MPs-associated gastric cancer
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Using gene databases, patient tumor data, and human gastric cancer cells in lab tests, researchers studied how PET microplastics may contribute to gastric cancer. They identified two genes, PIM1 and NOX4, linked to cancer progression, and found that blocking PIM1 activity reduced microplastic-driven cell growth and spread in lab-grown cells.
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.
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