Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals widely used in consumer products, food packaging, and firefighting foams, notorious for their persistence in the environment and the human body. Recent research conducted by the Keck School of Medicine at the University of Southern California (USC) sheds light on the complex ways these chemicals impair liver function at the cellular level, providing unprecedented insight into how different PFAS compounds contribute to liver disease and potential cancer development. This study, published in the journal Environment International, leverages cutting-edge 3D liver models derived from human cells, marking a significant advance in environmental toxicology and human health research.
The liver’s critical role in detoxifying the bloodstream makes it exceptionally vulnerable to toxic insults from PFAS. These “forever chemicals,” as they are often termed due to their resistance to degradation, accumulate over many years, raising concerns about long-term health consequences including liver damage and metabolic disruptions. Despite epidemiological evidence linking PFAS exposure to liver abnormalities, including steatosis and cancer, the precise cellular and molecular mechanisms remained incompletely understood until now, largely due to limitations in traditional animal and cell culture models.
To overcome these challenges, researchers turned to human liver spheroids—a sophisticated three-dimensional culture system that closely mimics the architecture and microenvironment of the human liver. Made from cells pooled from multiple donors, these spheroids preserve critical cell-cell interactions that drive normal liver functions and pathological responses. This platform allowed for a nuanced investigation into the effects of four prevalent PFAS compounds—perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), perfluorooctanesulfonic acid (PFOS), and perfluorononanoic acid (PFNA)—each tested independently to discern their unique toxicity profiles.
After a continuous seven-day exposure of liver spheroids to these PFAS compounds, researchers employed advanced single-cell RNA sequencing to unravel gene expression changes at an unprecedented resolution. This technique revealed that while all four PFAS disrupt immune signaling pathways and interfere with intercellular communication—processes essential for liver homeostasis—their downstream effects diverged significantly. For instance, PFOA and PFHxS both promoted abnormal fat accumulation in liver cells, yet they achieved this through distinct mechanisms: PFOA stimulated de novo lipogenesis, increasing fat synthesis, whereas PFHxS inhibited fat metabolism, causing retention of lipids within cells.
Conversely, exposure to PFOS and PFNA led to gene expression patterns linked to oncogenic transformation. Notably, PFNA demonstrated a pronounced effect in activating pathways associated with inflammation, oxidative stress, and DNA repair mechanisms—hallmarks of cellular stress that can precipitate malignant transformation. The startling discovery that 61.3% of PFNA-exposed liver cells exhibited cancer-related gene signatures underscores the grave risk this compound poses to liver health, potentially accelerating the progression towards hepatocellular carcinoma.
Intriguingly, the study uncovered sex-specific differences in liver cell responses to PFAS exposure. Female-derived liver cells exhibited heightened sensitivity to PFOA, whereas male-derived cells were more affected by PFOS. These findings hint at underlying biological pathways modulated differently across sexes, suggesting the need for sex-informed strategies in both risk assessment and therapeutic development. Such differential susceptibility could be rooted in hormonal influences, enzyme expression profiles, or genetic regulatory networks that modulate PFAS metabolism and cellular stress responses uniquely in males and females.
The implications of this research extend far beyond the laboratory. By illuminating the precise cellular pathways disrupted by individual PFAS compounds, the study provides a critical foundation for the design of targeted interventions. Some pharmaceutical agents that modulate lipid metabolism and inflammation—already approved by the U.S. Food and Drug Administration—emerge as promising candidates for repurposing to ameliorate PFAS-induced liver toxicity. This represents a pivotal step towards translating mechanistic insights into clinical therapies that can reduce the burden of PFAS-related liver diseases.
Yet, despite therapeutic optimism, the researchers emphasize that prevention remains paramount. Reducing PFAS exposure is critical given their pervasive presence and persistent nature. They advise practical measures such as consuming filtered water and avoiding products coated with PFAS, including nonstick cookware. Although regulatory efforts are underway globally, immediate individual actions offer a necessary line of defense against these insidious chemicals, whose harm continues to unfold silently within our bodies.
This investigation is part of the Southern California Superfund Research and Training Program for PFAS Assessment, Remediation and Prevention (ShARP Center), a multidisciplinary NIH-funded initiative committed to addressing the environmental and health challenges posed by PFAS contamination. By fostering collaboration across toxicology, environmental science, and public health, the ShARP Center aims to generate actionable knowledge and innovative solutions that can safeguard communities affected by PFAS pollution.
Future directions for this research involve exploring the combined effects of multiple PFAS compounds, reflecting real-world exposure scenarios where humans encounter complex mixtures rather than single substances. This line of inquiry is crucial because PFAS mixtures may exhibit synergistic or additive toxicities that differ from individual chemicals, further complicating risk assessment and regulatory standards. Understanding these interactions at the granular cellular level will be key to refining safety guidelines and developing effective mitigation strategies.
The technical achievements in this study—particularly the use of multi-donor human liver spheroids paired with single-cell transcriptomics—represent a breakthrough for toxicological research. This approach enables scientists to disentangle heterogeneous cellular responses, map molecular pathways with fine detail, and capture subtle variations linked to donor sex or genetic background. Such methodological innovations are setting new standards for environmental health research, transcending the limitations of animal models and traditional cell cultures.
As PFAS contamination continues to be a pressing environmental health issue worldwide, this research highlights the urgent need for informed public health policies and consumer awareness. The distinct molecular fingerprints left by different PFAS chemicals in liver cells not only clarify their individual toxicities but also underscore the complexity of their impact on human health. Accurate, mechanistic knowledge is indispensable for crafting nuanced regulations that protect vulnerable populations while guiding the development of medical interventions.
In sum, this comprehensive study advances our understanding of how perfluoroalkyl substances sabotage liver health at the most fundamental biological levels. Through innovative research techniques and a focus on translational impact, the USC team has transformed the opaque landscape of PFAS toxicity into a clearer map of cellular disruption, risk, and potential remedy. Their work will resonate across toxicology, medicine, and environmental science communities for years to come, fueling efforts to combat the global challenge posed by these persistent pollutants.
Subject of Research: Cells
Article Title: Assessing the impact of perfluoroalkyl substances on liver health: a comprehensive study using multi-donor human liver spheroids
News Publication Date: 5-Sep-2025
Web References:
https://www.sciencedirect.com/science/article/pii/S0160412025005148
http://dx.doi.org/10.1016/j.envint.2025.109763
References:
Maretti-Mira, A. C., Golden-Mason, L., Matsuba, C., Wang, Y., Salomon, M. P., Setiawan, V. W., & Chatzi, L. (2025). Assessing the impact of perfluoroalkyl substances on liver health: a comprehensive study using multi-donor human liver spheroids. Environment International, [DOI:10.1016/j.envint.2025.109763].
Keywords:
Liver damage, Liver cancer, Metabolic disorders, Chemical pollution, Water pollution, Pollutants, Fatty liver disease
