Translational framework linking perfluoroheptanoic acid (PFHpA) exposure to metabolic dysfunction associated steatotic liver disease in adolescents

The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), particularly among pediatric populations, requires identification of modifiable risk factors to control disease progression. Per- and polyfluoroalkyl substances (PFAS) have emerged as potential contributors to liver damage; however, their role in MASLD remains underexplored. This study aimed to develop a translational framework integrating human and in vitro data to elucidate the effect of PFAS on MASLD development. We measured PFAS plasma levels in the Teen-LABS cohort (n = 136), comprising adolescents with obesity (mean age = 16.8 years) undergoing bariatric surgery. Plasma samples were also analyzed using proteomic and metabolomic assays. MASLD was diagnosed by liver biopsy examination. Human liver spheroids were exposed to perfluoroheptanoic acid (PFHpA) in vitro and analyzed by single-cell transcriptomics. The latent unknown clustering with integrated data (LUCID) model was employed to assess associations between PFHpA exposure, multiomic signatures, and MASLD risk. Here we show that, among all PFAS measured, doubling of PFHpA levels is associated with an 80% higher MASLD risk (OR, 1.8; 95% CI: 1.3–2.5). Integrated human and in vitro analyses suggest dysregulation of pathways involved in inflammation and lipid metabolism. A distinct proteome profile is associated with significantly higher odds of MASLD (OR = 7.1). This study offers evidence implicating PFHpA, a short-chain unregulated PFAS congener, in MASLD development in adolescents, and highlights the critical role of protein dysregulation in disease pathogenesis. The molecular mechanisms identified here can inform the development of targeted prevention and treatment strategies. Baumert, Maretti-Mira et al. integrate human epidemiological data and in vitro liver spheroid models to investigate PFHpA, an unregulated PFAS, in adolescent MASLD. Findings link PFHpA exposure to increased disease risk and identify key pathogenic mechanisms and potential therapeutic targets. Metabolic dysfunction–associated steatotic liver disease (MASLD) is a form of fatty liver disease not caused by heavy alcohol use. It includes a more severe condition, MASLD-associated steatohepatitis (MASH), where liver inflammation and damage occur. The growing number of children affected by MASLD highlights the urgent need to identify environmental and lifestyle factors that may worsen the disease. This study examined the role of perfluoroheptanoic acid (PFHpA), a type of per- and polyfluoroalkyl substance (PFAS), in MASLD. PFAS are man-made chemicals widely used by industrial processes and consumer products, and nearly everyone in the United States has detectable levels of PFAS in their blood. We found that higher PFHpA levels were linked to greater risk of MASLD and worsen disease severity. These findings provide important evidence for researchers, clinicians, and public health officials. Understanding how PFAS contribute to liver disease may help shape prevention strategies, guide policies that limit exposure, and support precision health approaches to protect children and other vulnerable groups.