Perfluorodecanoic Acid Induces Metabolic Dysfunction‐Associated Steatotic Liver via the FTO/m ⁶ A/IL18/ADIRF‐Mediated Lipogenesis Pathway and the Protective Effect of Dietary Folic Acid

ABSTRACT Perfluorodecanoic acid (PFDA) is a pervasive food chemical contaminant which is readily absorbed and accumulated in the liver. This study aimed to investigate the adverse effects of PFDA exposure on metabolic dysfunction‐associated steatotic liver (MASL) and to explore the potential protective role of dietary folic acid. Utilizing data from the National Health and Nutrition Examination Survey, we first observed that PFDA exposure exhibited the strongest association with metabolic dysfunction‐associated steatotic liver disease (MASLD) risk among all detected perfluoroalkyl and polyfluoroalkyl substances in the general population, whereas high folic acid consumption could potentially mitigate this risk. Further in vivo experiments indicated that PFDA exposure‐induced MASL in C57BL/6 mice, characterized by elevated serum and hepatic levels of TC, TG, LDL‐c, and HDL‐c, as well as an increased LDL‐c/HDL‐c ratio. In vitro experiments demonstrated that PFDA exposure induced cellular steatosis by promoting lipogenesis and oxidative stress in hepatocytes. Mechanistically, PFDA exposure reduced the m 6 A modification of IL18 mRNA by upregulating FTO, thereby shielding it from YTHDF2‐mediated degradation. Elevated IL18, in turn, promoted lipogenesis by upregulating ADIRF. Ultimately, folic acid supplementation mitigated PFDA‐induced MASL both in vivo and in vitro. Collectively, these findings suggest that PFDA induces MASL via FTO/m 6 A/IL18/ADIRF‐mediated lipogenesis, and that adequate dietary folic acid supplementation may be a promising strategy to counteract this foodborne toxicity.