Perfluorobutanesulfonic acid (PFBS) elicits compartment-specific divergent responses in prostate homeostasis: Wnt/(3-catenin oncogenic activation in epithelial cells versus mitochondria-mediated ferroptosis susceptibility in stromal cells

초록

Perfluorobutanesulfonic acid (PFBS), a short-chain per- and polyfluoroalkyl substance (PFAS) adopted as a replacement for perfluorooctane sulfonate (PFOS), is ubiquitously detected in environmental matrices and human biological samples. Despite growing regulatory concern, the molecular mechanisms by which PFBS affects prostate tissue at environmentally relevant concentrations remain poorly characterized. In the present study, we exposed human prostate epithelial (RWPE-1) and stromal (WPMY-1) cells to PFBS (0-100 nM, 24 h) and integrated in vitro mechanistic analyses with genome-wide RNA sequencing (RNA-seq), Gene Ontology (GO) enrichment, KEGG pathway analysis, and protein-protein interaction (PPI) network clustering. At concentrations maintaining cell viability above 80%, PFBS induced opposing responses in the two cell types. In RWPE-1 epithelial cells, PFBS activated the PI3K-AKT-GSK3(3 axis with concurrent nuclear (3-catenin accumulation, upregulation of Wnt target genes, S-phase entry, and induction of an IGF-1/IGF-2 autocrine loop. In WPMY-1 stromal cells, PFBS suppressed the PI3K-AKT axis, induced G0/G1 arrest, caused approximately 400% ROS elevation, depolarized mitochondrial membranes, decreased GPX4, and upregulated ACSL4 and intracellular Fe2 + accumulation, collectively suggesting heightened ferroptosis susceptibility, along with reduced expression of stromal paracrine factors (FGF7, FGF10 and HGF). RNA-seq and bioinformatics analyses revealed markedly divergent transcriptional landscapes between two cell types. GO enrichment identified phospholipid metabolic process and Wnt signaling as the dominant RWPE-1 programs, and extrinsic apoptotic signaling and mitochondrion organization regulation in WPMY-1. These findings suggest that, under these in vitro conditions, PFBS can simultaneously activate Wnt signaling in epithelial cells and promote ferroptosis susceptibility in stromal cells, a divergent response pattern not captured by conventional single-endpoint toxicity assays. As these observations were obtained in isolated monocultures, they should be interpreted as cell-autonomous vulnerabilities that require validation in co-culture, organoid, and in vivo systems before any inference regarding human systemic risk can be drawn.

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