Developmental Environmental Chronotoxicity by Polystyrene Nanoplastics Exacerbates High‐Fat Diet‐Induced Pediatric MAFLD Through Circadian Disruption and Mitochondrial Dysfunction

Environmental nanoplastic exposure is increasingly recognized as a contributor to metabolic dysfunction, yet its impact on susceptibility to diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD) during development remains unclear. Here, we show that polystyrene nanoplastics (PS-NPs) exacerbate high-fat diet (HFD)-induced hepatic steatosis in an age-dependent manner. In juvenile, but not adult, mice, PS-NPs augmented HFD-driven dyslipidemia, hepatomegaly, and hepatic lipid accumulation without altering energy intake. Mechanistic analyses revealed disruption of the hepatic circadian-mitochondrial axis, including altered clock gene programs, impaired AMP-activated protein kinase (AMPK) signaling, mitochondrial dysfunction, and suppressed oxidative metabolism. In hepatocytes, PS-NPs potentiated free-fatty-acid-induced circadian misalignment, mitochondrial impairment, oxidative stress, and lipid accumulation. AMPK activation by AICAR alleviated steatosis and mitochondrial defects, whereas circadian modulation by SR9009 improved mitochondrial function and hepatocellular injury, highlighting distinct protective mechanisms. Collectively, these findings define early life as a critical window of vulnerability to combined environmental and dietary stressors and introduce the concept of chronotoxicity, the capacity of environmental exposures, such as PS-NPs, to perturb circadian timing and temporal metabolic organization-linking nanoplastic exposure to pediatric MAFLD.