Investigating the Potential Effects of F-53B on Pulmonary Arterial Hypertension Through Network Toxicology, Molecular Docking, and In Vitro Validation.

Pulmonary arterial hypertension (PAH) is a fatal vascular disorder with poor prognosis. 6:2 chloro-polyfluorooctane ether sulfonate (F-53B), a persistent environmental contaminant detected in humans, is known to be vasculotoxic, yet its association with PAH remains unexplored. This study aims to elucidate the mechanisms linking F-53B exposure to PAH by integrating network toxicology, molecular docking and in vitro experiments. Potential F-53B targets were predicted using ChEMBL, PharmMapper, and TargetNet. PAH-related genes were compiled from GeneCards, Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD), and GSE254617. We identified 42 key targets of F-53B-related PAH. Functional enrichment revealed terms such as inflammatory response and extracellular matrix. Protein-protein interaction (PPI) analysis identified five hub genes: CCL2, CXCL8, CCL5, CCR2, and CCL11. Molecular docking confirmed strong binding between F-53B and these core targets, with CCR2 showing the strongest affinity (-10 kcal/mol). Molecular dynamics simulations further verified stable binding to CCR2. In vitro experiments demonstrated that F-53B activated the CCL2/CCR2 axis and induced IL-1β, TNF-α, and IL-6 in HUVECs and RAW264.7 cells. This study reveals that F-53B is linked to PAH through dysregulation of chemokine signaling networks and induction of inflammatory cytokines. These findings suggest F-53B as a potential environmental risk factor for PAH and pinpoint potential targets for intervention.