The investigation arose from the analysis of blood samples collected from 137 adolescents enrolled in the Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS), the largest longitudinal study of pediatric bariatric surgery in the United States. Researchers identified that those adolescents exhibiting blood PFHpA concentrations twice as high as their counterparts faced an 80% greater probability of being diagnosed with MASLD. Moreover, these individuals demonstrated more advanced pathological hallmarks, including hepatic inflammation and fibrosis, which are established precursors to cirrhosis, liver failure, and hepatocellular carcinoma. This clinical association was substantiated through meticulous laboratory experiments employing PFHpA doses commensurate with real-world human exposure levels. Using 3D liver spheroids cultivated under controlled conditions, the team delineated how PFHpA disrupts critical biological pathways involving inflammatory signaling cascades, oxidative stress induction, and aberrant lipid metabolism, all converging to propagate hepatic injury. The synergy of patient-derived clinical data with rigorous in vitro modeling enabled the characterization of a unique molecular signature emblematic of PFHpA-mediated hepatotoxicity.

Metabolic dysfunction-associated steatotic liver disease, previously recognized as non-alcoholic fatty liver disease (NAFLD), remains one of the most prevalent hepatic conditions in children and adolescents nationwide, affecting about five to ten percent of this population and exceeding 30% prevalence among those with obesity. Alarmingly, MASLD incidence is climbing, portending severe complications such as type 2 diabetes mellitus and cardiovascular pathology. The identification of PFHpA as a contributory environmental factor exacerbating MASLD progression carries profound implications, especially given the ubiquitous presence of PFAS substances. Owing to their widespread use in consumer goods like food packaging, waterproof apparel, cosmetics, and non-stick cookware, PFAS contamination extends across numerous water supplies throughout the United States. Recent estimates indicate nearly half of all American municipal water systems contain measurable PFAS concentrations, underscoring the pressing public health challenge.

Dr. Lida Chatzi, MD, PhD, the study’s senior investigator and director of the ShARP Center, emphasized the significance of these findings, noting that “PFHpA, despite being less notorious than legacy PFAS such as PFOA and PFOS, likely poses comparable risks to human health.” Her call to action stresses the imperative for comprehensive regulatory frameworks that encompass emerging PFAS compounds alongside well-characterized legacy chemicals. This holistic regulatory approach is necessary to mitigate community exposures that continue unabated amid evolving chemical production landscapes.

The study’s translational framework exemplifies a robust integration of epidemiology and bench science. Brittney O. Baumert, PhD, MPH, lead author and postdoctoral fellow at USC, highlighted that “our research transcends correlative analyses, leveraging translational methodologies to elucidate the cellular and molecular perturbations induced by PFAS exposure.” By bridging clinical phenotypes with mechanistic data, the team aims to empower precision environmental health efforts that can identify and shield vulnerable groups—especially children and adolescents who bear heightened susceptibilities during critical windows of development.

Complementing this work, co-investigator Ana C. Maretti-Mira, PhD, led the in vitro studies that mapped PFAS activation of intracellular pathways within liver cells. “Decoding these pathways permits the identification of potential therapeutic targets to intervene before PFAS-related liver disease reaches irreversible stages,” she explained. This approach not only advances mechanistic understandings but also opens avenues for clinical interventions aimed at interrupting the progression from early hepatic injury to chronic liver disease.

Embedded within the broader mission of the USC Superfund Research Program, funded by the National Institute of Environmental Health Sciences (NIEHS), this research exemplifies a commitment to deciphering the health impacts of hazardous chemical exposures and translating findings into actionable prevention and policy. The USC team employed state-of-the-art exposomics technologies, including untargeted metabolomics, proteomics, and single-cell transcriptomics, to precisely characterize the molecular footprints of PFHpA exposure. Such sophisticated methodologies enable unprecedented resolution in linking environmental exposures to health outcomes, fostering a new era of precision environmental medicine.

Looking forward, the ShARP Center aims to extend its research to real-world community settings, focusing on the reduction of PFAS exposures through innovative engineering solutions and enhanced public engagement. Efforts will include the development of advanced PFAS remediation technologies, community education initiatives to raise awareness and behavioral modifications, as well as training programs to cultivate the next generation of environmental health scientists and engineers. These comprehensive strategies are integral to advancing precision health paradigms, where interventions can be tailored to individual risk profiles and environmental contexts to more effectively prevent chemical-mediated diseases.

The multi-institutional research team assembled for this study includes experts spanning the University of Southern California, Emory University, Barcelona Institute for Global Health, University of Rhode Island, Mount Sinai Icahn School of Medicine, University of California campuses, Northwestern University, Cincinnati Children’s Hospital Medical Center, Baylor College of Medicine, the National Cancer Institute, Children’s Hospital Los Angeles, and others. This collaborative network underscores the complexity of unraveling environmental health challenges and the necessity of cross-disciplinary expertise.

Funding sources supporting this work encompass a broad sweep of national and international agencies, reflecting the global urgency of addressing PFAS contamination and its health ramifications. These include the NIEHS, the National Institutes of Health (NIH), European Union exposome initiatives such as ATHLETE, California Environmental Protection Agency, and the U.S. Department of Agriculture. The diverse financial backing enables comprehensive research from molecular mechanistic studies to community-engaged interventions, fostering translational impact.

Conflict of interest disclosures reveal that while most authors report no conflicts, a few have consultancy relationships or advisory roles with pharmaceutical companies unrelated to this study, ensuring transparency. Notably, Dr. Bartell and Dr. Chatzi have provided expert assistance in legal cases involving PFAS exposures, reflecting their recognized expertise in this arena.

This landmark study fundamentally shifts our understanding of how lesser-known PFAS compounds like PFHpA contribute to childhood liver disease, a condition with rapidly escalating prevalence and severe long-term consequences. By illuminating molecular mechanisms and championing comprehensive research-to-policy pathways, it paves the way for targeted interventions to safeguard vulnerable youth globally, addressing a critical public health crisis with precision and urgency.

Subject of Research: Lab-produced tissue samples

Article Title: Translational Framework Linking Perfluoroheptanoic Acid (PFHpA) Exposure to Metabolic Dysfunction Associated Steatotic Liver Disease in Adolescents

News Publication Date: 29-Oct-2025

Web References:

• Southern California Superfund Research and Training Program for PFAS Assessment, Remediation and Prevention (ShARP) Center: https://sharpcenter.usc.edu/
• Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study: https://www.niddk.nih.gov/about-niddk/research-areas/obesity/bariatric-surgery-teens-severe-obesity-study-teen-labs
• Communications Medicine article DOI: http://dx.doi.org/10.1038/s43856-025-01168-z

References:
The original peer-reviewed publication in Communications Medicine (Nature Portfolio), along with cited funding grants and participating institutions detailed in the research disclosure.

Keywords: Liver damage, Fatty liver disease, Steatohepatitis, Liver cancer, Chemical pollution, Water pollution, Pollutants, Inflammation, Oxidative stress, Lipid metabolism

Dengue virus, a mosquito-borne flavivirus, continues to pose a formidable threat worldwide, particularly in tropical and subtropical regions. Despite decades of intensive research, effective therapeutic interventions remain scant, primarily hindered by the lack of physiologically relevant human models that mimic the intricate virus-host interactions. Traditional cell lines and animal models frequently fail to capture the nuanced pathology of dengue virus infection in human liver tissue, a critical site of viral replication and immune response modulation.

The research team, led by Li and colleagues, harnessed the remarkable differentiation potential of human pluripotent stem cells (hPSCs) to fabricate three-dimensional liver organoids. These miniaturized, self-organized tissue constructs recapitulate liver-specific architecture and functionality, exceeding the fidelity of conventional two-dimensional cultures. Importantly, these organoids demonstrated the capacity to model dengue virus infection accurately, reflected by robust viral replication, cytopathic effects, and host immune responses that parallel clinical observations.

Creating liver organoids from hPSCs involves meticulous orchestration of signaling pathways and growth factors guiding cells through early developmental stages toward hepatic lineage commitment. The resulting organoids, composed of hepatocyte-like cells embedded in a supportive extracellular matrix, exhibit hallmark liver functions, including albumin secretion and cytochrome P450 activity. This biochemical authenticity is vital to simulate the hepatic milieu in vivo, ensuring viral life cycle stages and host defense mechanisms unfold naturally.

Upon exposing the liver organoids to dengue virus, the research team observed dynamic infection kinetics characterized by escalating viral RNA levels over time, accompanied by morphological alterations indicative of cellular distress. Crucially, the infection elicited innate immune activation within the organoids, exemplified by the upregulation of interferon-stimulated genes and pro-inflammatory cytokines. This response mimics the antiviral defenses mounted by human liver cells during natural infection, underscoring the organoids’ physiological relevance.

The researchers also employed advanced imaging modalities to interrogate viral entry, assembly, and egress within the organoids. High-resolution confocal microscopy revealed the spatial distribution of dengue viral antigens co-localizing with hepatocyte markers, corroborating successful viral tropism and propagation. These insights into subcellular viral localization inform future therapeutic targeting strategies, potentially disrupting critical stages of the viral life cycle.

One of the study’s most transformative aspects lies in the liver organoids’ utility as a platform for antiviral drug screening. Existing dengue therapies are limited, and the emergence of resistance necessitates novel compounds assessed rigorously for efficacy and toxicity. The organoids provided a scalable, reproducible assay system wherein candidate antivirals could be evaluated against authentic human-like infection conditions. Several compounds tested demonstrated significant reductions in viral replication within the organoids without cytotoxicity, validated through quantitative PCR and cell viability assays.

Furthermore, the use of organoids circumvents ethical and scientific limitations of animal models, reducing reliance on non-human primates and enabling patient-specific studies. Given the donor-specific characteristics of hPSC lines, personalized liver organoids could model individual susceptibility and response to dengue virus, paving the way for precision medicine approaches in flavivirus infections.

The incorporation of transcriptomic analyses deepened understanding of host-pathogen interplay within the organoids. Differential gene expression profiling before and after infection highlighted pathways perturbed by dengue virus, including those regulating apoptosis, metabolism, and immune signaling. These molecular signatures serve as biomarkers for disease progression and offer targets for therapeutic intervention.

Importantly, the organoid model addresses a critical bottleneck in antiviral research by faithfully modeling the liver’s microenvironment, including cell-cell interactions and three-dimensional structure. Such complexity is imperative, as dengue pathogenesis involves not only viral cytotoxicity but also dysregulated immune responses and vascular leakage, processes partially orchestrated by hepatic cells. Future iterations of organoids may integrate additional cell types, such as Kupffer cells and endothelial cells, further enhancing model fidelity.

The implications of this research extend beyond dengue virus to other hepatotropic viruses, including hepatitis B and C viruses, where human-relevant infection models are similarly lacking. By establishing a versatile organoid platform, the study lays the foundation for broad-spectrum antiviral discovery and mechanistic studies of liver infections.

Challenges remain, particularly in scaling organoid production for widespread application and ensuring consistent maturation states that affect viral susceptibility. Nonetheless, continuous refinement of differentiation protocols and biomaterial scaffolds promises to enhance reproducibility and throughput, key factors for translational success.

In conclusion, the creation of human pluripotent stem cell-derived liver organoids marks a pivotal advance in infectious disease modeling. This approach enables detailed elucidation of dengue virus biology within authentic human tissue context and provides a robust tool for accelerating antiviral drug development. As dengue incidence escalates globally, innovations such as this provide critical ammunition in the fight against this insidious virus.

The study by Li et al. epitomizes the synergy of stem cell biology, virology, and bioengineering in confronting emergent infectious diseases. By bridging the gap between cellular models and clinical pathology, organoid technology stands to revolutionize how researchers investigate viral infections and translate findings into effective therapies for millions affected worldwide.

Subject of Research: Dengue virus infection modeling using human pluripotent stem cell-derived liver organoids and antiviral drug screening.

Article Title: Recapitulating dengue virus infection with human pluripotent stem cell-derived liver organoids for antiviral screening.

Article References:
Li, MQ., Xu, YP., Li, K. et al. Recapitulating dengue virus infection with human pluripotent stem cell-derived liver organoids for antiviral screening. Nat Commun 16, 8069 (2025). https://doi.org/10.1038/s41467-025-63323-3

Image Credits: AI Generated