Multidimensional transcriptomic analysis and in vitro experiments dissect the landscape of 2',2',4',4'-Tetrabromodiphenyl ether in bladder cancer progression.

2',2',4',4'-Tetrabromodiphenyl ether (BDE-47), the most widespread congener of polybrominated diphenyl ethers, has attracted considerable attention due to its environmental persistence and extensive use. Although epidemiological data associate BDE-47 exposure with increased cancer risk, its role in bladder cancer (BC) remains insufficiently characterized. We found that BDE-47 at a physiologically relevant concentration (0.1 μM, comparable to human exposure levels) enhanced malignant phenotypes of BC cells in vitro. A total of 229 candidate genes were uncovered at both bulk and single-cell transcriptomic levels through weighted gene co-expression network analysis and its single-cell extension. Functional enrichment revealed prominent involvement in inflammatory regulation, extracellular matrix remodeling, and lipid metabolism pathways, further supported by transcriptome analysis of BDE-47-treated BC cells. Protein-protein interaction network construction combined with machine learning identified eight hub genes (ACSL4, IFIH1, JAK2, PSMB9, ACSL5, SOCS3, SREBF1, and JUN) as core targets of BDE-47-driven BC progression. Molecular docking suggested favorable predicted interactions between BDE-47 and these targets. A nomogram was constructed within the TCGA-BLCA cohort to visualize the prognostic model. Collectively, our findings provide a preliminary delineation of candidate targets and pathways potentially involved in BDE-47-associated bladder cancer progression, thereby offering a rationale for further mechanistic investigations.