Forever chemical PFHpA is a risk factor for severe liver disease in adolescents

Scientists at the Keck School of Medicine of USC, working within the Southern California Superfund Research and Training Program for PFAS Assessment, Remediation and Prevention (ShARP) Center, have uncovered compelling evidence that exposure to perfluoroheptanoic acid (PFHpA), a lesser-known member of the PFAS family of ‘forever chemicals’, is linked to a significantly higher risk and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) in adolescents with obesity.

Perfluorooctanoic acid (PFOA) visible through a glovebox window in an emulsion (Credit: North747)

"PFHpA is not as well-known as the legacy PFAS like PFOA or PFOS, but our findings show it may pose comparable risks to human health," said the study's senior author, Dr Lida Chatzi, professor of population and public health sciences and director of the ShARP Center at the Keck School of Medicine. "This underscores the urgency of regulating not just the PFAS compounds we already know a lot about, but the broader class of emerging chemicals that communities are being exposed to every day."

The study integrates clinical data from adolescents undergoing bariatric surgery with advanced 3D liver models to reveal the biological mechanisms by which PFHpA may drive disease progression. The researchers examined blood samples from 137 adolescents enrolled in Teen Longitudinal Assessment of Bariatric Surgery, the largest US study of paediatric bariatric surgery.

They found that adolescents with twice the amount of PFHpA in their blood faced an 80% greater likelihood of being diagnosed with MASLD compared to their peers with lower levels. Teens with higher exposures also showed more advanced liver injury, including inflammation and fibrosis—early signs of disease progression that can eventually lead to cirrhosis, liver failure, or even liver cancer.

To strengthen these findings, the team tested PFAS on laboratory-grown liver spheroids using doses comparable to typical human exposure, showing that PFHpA disrupts critical biological pathways, including inflammation, oxidative stress and lipid metabolism. This dual approach allowed the researchers to connect exposure to the mechanism, producing a distinctive molecular signature of PFHpA-related liver damage.

MASLD, once referred to as nonalcoholic fatty liver disease, is one of the most common liver disorders in young people, affecting an estimated five to 10% of US children and adolescents and more than 30% of those with obesity. It is also a condition on the rise, placing many young people at risk of severe long-term health consequences, including type 2 diabetes and cardiovascular disease.

The fact that exposure to PFHpA can worsen this trajectory is particularly concerning given how widespread these chemicals are. PFAS are used in products ranging from food packaging and waterproof clothing to cosmetics and nonstick cookware, and they contaminate drinking water supplies across the country. Nearly half of all U.S. water systems are now believed to contain detectable PFAS levels.

"Our research goes beyond simple associations," said Dr Brittney O Baumert, lead author and postdoctoral fellow at USC. "Using a translational science approach by bridging bench science and epidemiological research, we are uncovering how these chemicals alter liver biology at the cellular level. That knowledge can ultimately help us protect vulnerable populations, especially children and adolescents."

This study reflects the mission of the USC Superfund Research Program to uncover the health impacts of hazardous chemicals and translate discoveries into prevention and policy. By integrating patient-based data with advanced exposomics technologies such as metabolomics, proteomics and single-cell transcriptomics, USC researchers are bridging laboratory science and public health.

"By mapping the pathways PFAS activate inside liver cells, we can pinpoint potential therapeutic targets to help stop PFAS-induced liver disease before it progresses,” added Dr Ana C Maretti-Mira, who led the in vitro experiments.

Looking ahead, the ShARP Center will focus on reducing PFAS exposures in real-world communities. Future ShARP Center projects will advance engineering innovations for PFAS treatment, increase community engagement efforts to raise awareness about exposure pathways and strategies for reducing risk, and train the next generation of environmental health and engineering scientists.

A central goal of all these studies is to advance the fields of precision environmental health and precision medicine, ensuring that research findings can be translated into targeted interventions, personalized prevention strategies and evidence-based policies that protect the most vulnerable.

The findings were featured in the paper, ‘Translational Framework Linking Perfluoroheptanoic Acid (PFHpA) Exposure to Metabolic Dysfunction Associated Steatotic Liver Disease in Adolescents’, published in Communications Medicine. To access this paper, please click here