Hypothesis-generating network toxicology analysis of potential molecular convergence between a polystyrene oligomer proxy and papillary thyroid carcinoma

Background Polystyrene microplastics (PS-MPs) are emerging environmental contaminants with endocrine-disrupting and pro-inflammatory effects, but whether PS-MPs-associated molecular targets converge with papillary thyroid carcinoma (PTC) alterations remains unclear. This hypothesis-generating study aimed to identify candidate molecular networks and cellular contexts shared between a simplified polystyrene computational proxy and PTC. Methods Putative targets from CTD and from TargetNet/SwissTargetPrediction using a five-styrene-unit oligomer proxy were intersected with thyroid cancer-related genes from OMIM and GeneCards. Protein functional-association and enrichment analyses were followed by differential expression analysis in GSE33630 (45 normal and 49 PTC samples). LASSO and SVM-RFE identified core genes; stability was examined by repeated nested resampling conditional on the seven-gene candidate panel. Individual-gene tumor-normal discrimination was assessed in GSE33630 and GSE60542. Protein patterns were evaluated qualitatively in the Human Protein Atlas and preliminarily in 15 matched PTC-adjacent tissue pairs. CIBERSORT-estimated immune fractions and two single-cell datasets were analyzed as exploratory context. Results Among 144 putative proxy-associated targets and 2,139 thyroid cancer-related genes, 75 were shared. Seven candidates overlapped with 1,306 PTC differentially expressed genes, and BCL2, BAX, and FN1 were selected by both feature-selection methods and remained stable across the tested GeneCards thresholds and CTD-only sensitivity analysis. BCL2 was downregulated, whereas BAX and FN1 were upregulated in PTC; individual-gene AUCs were 0.963, 0.941, and 0.965 in GSE33630 and 0.942, 0.907, and 0.955 in GSE60542. HPA images and clinical IHC supported the same protein-level directions. After multiple-testing correction, only the CIBERSORT-estimated neutrophil fraction differed between groups (higher in PTC; q=0.0021). Single-cell analysis localized the three genes across epithelial, stromal, and immune compartments. Conclusion BCL2, BAX, and FN1 are candidate molecular nodes at the convergence of polystyrene-proxy annotations and PTC-associated alterations. The findings do not demonstrate patient PS-MPs exposure, intact-particle effects, or causality, and require validation in material-characterized exposure experiments and exposure-aware clinical studies.