To Örebro University

Background and aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, yet excess adiposity alone does not explain interindividual susceptibility or disease progression. Environmental exposures, particularly endocrine-disrupting chemicals such as per- and poly-fluoroalkyl substances (PFAS), may act as disease modifiers by exacerbating metabolic stress and impairing hepatic adaptive capacity. Our aim was to identify associations between real-life chemical exposures and MASLD severity and to study underlying metabolic pathways relevant to liver pathology.

Method: We performed an exposome-wide analysis in 1,521 adults from the European Steatotic Liver Disease (SLD) Registry, covering the spectrum of steatosis, inflammation, and fibrosis. Plasma PFAS and metabolic profiles were analysed using liquid chromatography–mass spectrometry. Associations with liver-related phenotypes were assessed using multivariable and sex-stratified analyses. Findings were combined with PFAS exposure experiments in mice and hepatocyte-like HepaRG cells to support mechanistic interpretation.

Results: PFAS and parabens were associated with MASLD severity, correlating with histologically characterised steatosis, ballooning, and fibrosis, with non-invasive fibrosis measures (fib4 and fibroscan) as well as markers of insulin resistance in sex-specific manner. PFAS exposure was linked to disturbances in bile acid metabolism, lipid metabolism (phosphatidylcholines and sphingolipids), amino acids and gut microbiota–derived metabolites, with stronger associations in males. Upregulation of several bile acids was also associated with fibrosis, especially in males (9 bile acids with adjusted p < 0.1, t >2.8), and with lipids in both females and males (182 and 167 lipids in females and males, respcectly, adj. p < 0.01). These metabolic signatures were directionally consistent across human, in vivo, and in vitro models and were most pronounced under steatotic conditions, suggesting synergistic effects.

Conclusion: Integrated human and experimental data indicate that PFAS exposure is associated with more advanced MASLD through disruption of bile acid homeostasis, lipid metabolism, mitochondrial pathways, and the gut–liver axis. Environmental chemical exposure may therefore represent a clinically relevant modifier of MASLD progression, supporting the inclusion of exposome-informed perspectives in risk stratification and preventive strategies in hepatology.