Health hazards of per- and polyfluoroalkyl substances via nuclear receptors

Per- and polyfluoroalkyl substances (PFAS) are highly persistent environmental contaminants that lead to continuous human exposure, posing a major global public health concern. However, the multisystem effects at the molecular level remain insufficiently understood. This review positions the nuclear receptor (NR) superfamily as a central regulatory hub linking PFAS exposure to multi-organ toxicity. First, we characterize the in vivo behavior of PFAS under realistic mixed-exposure scenarios, highlighting the limitations of traditional toxicological models based on single compounds and linear dose-response relationships in capturing complex biological effects across tissues and receptor systems. We then systematically integrate current evidence on PFAS interactions with key nuclear receptors, including peroxisome proliferator-activated receptor α/γ (PPARα/γ), estrogen receptor (ER)/androgen receptor (AR), constitutive androstane receptor (CAR)/pregnane X receptor (PXR), aryl hydrocarbon receptor (AhR), and glucocorticoid receptor (GR). Mechanistically, PFAS can modulate receptor activity through direct binding to ligand-binding domains, alteration of cofactor recruitment, and changes in chromatin accessibility. These interactions subsequently disrupt lipid metabolism, bile acid homeostasis, glucose regulation, inflammatory signaling and endocrine pathways. By integrating findings from animal models and human epidemiological studies, we further link these molecular perturbations to adverse outcomes such as dyslipidemia, impaired glucose homeostasis, immune dysfunction, and renal carcinogenesis, emphasizing inter-organ crosstalk mediated by metabolic and hormonal networks. Finally, we highlight current knowledge gaps and propose that integrating multi-omics approaches, receptor-specific models, and standardized exposure assessment frameworks will strengthen causal inference and support more predictive risk assessment strategies for PFAS-related health effects.