BCAT1 mediates the carcinogenic effects of environmental bisphenol exposure: mechanistic discoveries in osteosarcoma and pan-cancer analysis.

Bisphenols (including BPA, BPF, BPS, BPAF and TBBPA) are ubiquitous environmental endocrine disruptors linked to increased risk of multiple malignancies, yet their carcinogenic mechanisms remain poorly understood. To address this gap, the present study aimed to elucidate how bisphenols drive osteosarcoma initiation and progression, identify core mediating targets, and explore their pan-cancer relevance. We integrated network toxicology with osteosarcoma transcriptome datasets to screen hub genes, validated candidates via independent cohorts and machine learning, and pinpointed the core target through combined SHapley Additive Explanations (SHAP) and Weighted Gene Co-expression Network Analysis (WGCNA). Using data from The Cancer Genome Atlas (TCGA), we analyzed the target's association with osteosarcoma patient survival, while reverse transcription quantitative polymerase chain reaction (RT-qPCR), RNA sequencing (RNA-seq), and Western blotting confirmed its differential expression in osteosarcoma cell lines versus normal osteoblasts. Additionally, we performed simulated BCAT1 gene knockout using scTenifoldKnk to investigate its regulatory effects on downstream gene networks. Molecular docking and all-atom molecular dynamics simulations assessed bisphenol-target binding affinity, complemented by comprehensive pan-cancer analyses of public omics databases. Bioinformatic analyses identified branched-chain amino acid transaminase 1 (BCAT1) as the key regulatory gene, with experimental validation confirming its marked upregulation in osteosarcoma cells. All five bisphenols exhibited high binding affinity for BCAT1 in structural simulations, and pan-cancer analysis revealed BCAT1 overexpression in multiple solid tumors, correlating with unfavorable clinical outcomes. Collectively, these findings suggest that bisphenols may act as potential regulators of BCAT1, with implications for tumor progression, though further experimental validation is required to confirm the actual enzymatic activity modulation and carcinogenic effects.