Per- and polyfluoroalkyl substances (PFAS) suppress macrophage alternative activation to disrupt hepatic lipid metabolism [RNA-seq II]

Per- and polyfluoroalkyl substances (PFAS) are pervasive environmental pollutants with diverse toxic effects, including endocrine disruption and hepatotoxicity. As a key class of immune cells, macrophages are critical target for endocrine disrupting chemicals (EDCs); however, their role in PFAS-induced toxicity and the underlying mechanisms remain poorly understood. In this study, we developed a high-content cell model by utilizing the activation and differentiation of human THP-1 monocytes into macrophages, enabling rapid quantitative screening of various PFAS chemicals. Our results identified that PFOA, PFUnDA, and HFPODA suppressed macrophage alternative activation to varying extents by disrupting the PPAR signaling pathway. In vivo, oral exposure to PFOA and PFUnDA in wild-type C57BL/6J mice significantly impaired macrophage alternative activation in the liver, resulting in hepatocyte hypertrophy, liver dysfunction, and systemic lipid metabolism disorders. Furthermore, macrophage-specific PPARγ knockout exacerbated PFAS-induced hepatotoxicity. These findings highlight the immunometabolic regulatory role of macrophage activation in PFAS-induced liver toxicity and provide novel insights into the health risks posed by PFAS exposure in humans.