An integrative analysis reveals the mechanism of plastic stabilizers inducing breast cancer.

Plastic stabilizers (PSs) are chemical additives that are widely used to inhibit the degradation of plastics. However, their safety concerns and potential carcinogenic risks remain unclear. This study employed network toxicology strategies to elucidate the potential toxic effects and underlying molecular mechanisms of representative PSs, including 2,6-di-tert-butylphenol (2,6-DTB), tert-butylhydroquinone (TBHQ), and 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV-328) in breast cancer (BC). Herein, we identified 69 potential genes related to PSs exposure and BC, and optimized five core targets: GSK3B, MAPK14, PARP1, PIM1, and TRDMT1, through subsequent LASSO and SVM algorithms. Based on these core genes, we constructed risk score and nomogram models, both of which revealed that high expression of these five core genes predicts poor prognosis in BC patients. Additionally, molecular docking and dynamic simulations indicated high-affinity interactions between PSs and these core targets (binding energies < -5 kcal/mol). Further correlation analysis with prediction analysis of microarray 50 (PAM50) revealed increased expression of all core genes in the basal-like subtype, especially PIM1 and TRDMT1, which also exhibited the highest risk scores. In vitro, PSs transcriptionally upregulated MAPK14, PIM1, and TRDMT1, with STAT3 mediating their transcription. Importantly, cell counting kit-8 and wound healing assays demonstrated that PSs promote BC cell proliferation and migration. Our research re-evaluates the carcinogenic risks of plastic stabilizers and suggests that PSs may enhance breast cancer progression via targets such as MAPK14, PIM1, and TRDMT1. This study introduces a new approach for evaluating the safety of plastic additives and offers novel insights into the toxicological effects of PSs.