Mechanistic insights into BDE-153-induced idiopathic pulmonary fibrosis through network toxicology, machine learning,...

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. Polybrominated diphenyl ethers (PBDEs) are persistent environmental pollutants, yet whether the dominant human congener, 2,2',4,4',5,5'-hexabromodiphenyl ether (BDE-153), drives IPF-related molecular changes remains unclear. Here, we integrated network toxicology, machine learning, immune infiltration analysis, molecular docking, and targeted in vitro validation to explore molecular links between BDE-153 and IPF. A total of 436 overlapping targets were identified from 1185 BDE-153-related targets and 5787 IPF-associated genes. Functional enrichment highlighted AGE-RAGE, sphingolipid signaling, and apoptosis. Three core genes (BCL2, ESR1, and MAPK1) were prioritized as candidates and exhibited differential expression in IPF tissues, with area under the curve values of 0.777-0.917. Transcriptome-based immune infiltration analysis revealed associations of these core genes with altered infiltration of multiple immune cell types. Molecular docking suggested favorable BDE-153 binding to the three core proteins, especially ESR1. BDE-153 upregulated the expression of ESR1, α-SMA, IL-6, IL-8, and IL-1β in vitro, while ESR1 antagonist intervention further increased IL-8 secretion, indicating context-dependent inflammatory regulation. Collectively, these findings indicate that BDE-153 may modulate pro-inflammatory and fibrotic remodeling responses closely relevant to IPF pathogenesis, providing a hypothesis-generating basis for further mechanistic investigation.