Dissecting the molecular pathways through which long-chain PFAS disrupts dendritic cell maturation

Among the affected genes, pyruvate dehydrogenase kinase 4 (PDK4) emerged as a robust marker of PFAS-induced metabolic reprogramming. Functionally, PFAS exposure reduced expression of HLA-DR isotype, a key marker of DC maturation, with PFOA showing greater potency than the other compounds tested. Pharmacological inhibition experiments demonstrated that both PPARα-associated and GR-associated mechanisms contribute to the observed phenotype, although neither pathway alone fully accounted for the impairment.

Overall, these findings indicate that PFAS disrupt DC maturation through coordinated immunometabolic reprogramming involving interconnected nuclear receptor signaling pathways, providing mechanistic support for the immunotoxic effects associated with PFAS exposure.