Toxicol Appl Pharmacol. 2026 Jul 19:117964. doi: 10.1016/j.taap.2026.117964. Online ahead of print.
ABSTRACT
Congenital heart disease is a leading cause of infant death, arising from genetic and environmental factors. GenX, a replacement for legacy pollutants, is now a widespread contaminant. However, its cardiovascular risks are poorly understood. This study integrated network toxicology and experimental models to investigate the mechanisms of GenX-induced heart defects, focusing on its interaction with genes linked to common CHD subtypes. Network toxicology analysis, including protein-protein interaction network construction, hub gene identification, and functional enrichment, prioritized the JAK2-STAT3 signaling pathway for focused mechanistic validation, with JAK2 as the central candidate. Molecular docking suggested that GenX can bind to the JAK2 catalytic region, and ruxolitinib was used as a positive-control reference compound to benchmark the predicted JAK2 binding site. Subsequent molecular dynamics simulations demonstrated the stability and key interaction dynamics of the GenX-JAK2 complex. The experimental validation was performed in vivo and in vitro. Exposure of transgenic zebrafish larvae Tg(myl7:eGFP) and Tg(flk1:eGFP) to a tiered GenX concentration range, including an environmentally relevant concentration and higher exploratory concentrations, resulted in cardiac malformations, including pericardial edema and looping defects, alongside impaired vascular integrity. In human AC16 cardiomyocytes and zebrafish larvae, GenX exposure inhibited JAK2-STAT3 axis phosphorylation and activation, leading to increased caspase-3 activity and apoptotic cell death. Crucially, co-treatment with the JAK2 agonist butyzamide effectively rescued the signaling suppression and apoptotic phenotype induced by GenX. Our findings establish, for the first time, that the emerging contaminant GenX exerts cardiovascular developmental toxicity by directly targeting and inhibiting the JAK2-STAT3 pathway. This study delineates a novel molecular mechanism and identifies JAK2 agonism as a potential countermeasure against the cardiac hazards posed by this widespread environmental PFAS.
PMID:42472615 | DOI:10.1016/j.taap.2026.117964