HFPO-TA induces cardiac developmental damage in zebrafish by disrupting mitochondrial dynamics through FABP3

Hexafluoropropylene oxide trimer acid (HFPO-TA), a widely used substitute for perfluorooctanoic acid (PFOA), has raised concerns about potential cardiotoxicity. The study investigated mechanisms underlying HFPO-TA-induced cardiac developmental toxicity. Network toxicology and molecular docking identified the peroxisome proliferator-activated receptor (PPAR) signaling and fatty acid-binding protein-3 (FABP3) as key targets. In zebrafish embryos, HFPO-TA exposure caused pronounced cardiac developmental toxicity, indicated by pericardial edema, increased heart rate, and downregulated cardiac development genes (gata4, nkx2.5, sox9b, vmhc). Mechanistic analyses showed that HFPO-TA upregulated FABP3 while suppressing PPARγ and its coactivator PGC-1α. These changes disrupted mitochondrial dynamics by inhibiting fusion-related factors (Mfn1, Mfn2, Opa1) and enhancing fission-related factors (Drp1, Fis1), which further promoted apoptosis. Notably, CRISPRi-mediated FABP3 knockdown alleviated cardiac malformations, improved cardiac developmental gene expression, restored PPAR pathway activity, rebalanced mitochondrial dynamics, and reduced apoptosis. Collectively, HFPO-TA induces cardiac developmental toxicity via FABP3 activation, suppression of the PPARγ/PGC-1α axis, mitochondrial dynamics imbalance, and apoptosis. FABP3 represents a pivotal regulator in HFPO-TA-induced cardiac developmental toxicity and provides toxicological evidence supporting potential intervention targets for congenital heart disease.