PFAS and liver cancer: linking epidemiological evidence with mechanistic studies

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, and has a dismal five-year survival rate of 22%, making it one of the most fatal cancers. While hepatitis virus-related HCC is declining, the incidence of non-viral metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC is rising and is projected to become the leading cause of liver cancer. Growing evidence suggests that environmental chemical exposures contribute to liver cancer risk by promoting chronic inflammation, fibrosis, and metabolic dysfunction, yet these factors remain underexplored. Per- and polyfluoroalkyl substances (PFAS) are persistent ubiquitous chemicals and have emerged as potential risk factors for liver damage. However, their impact on the etiology of MASLD and HCC remains largely unexplored. In response to PAR-22-083 “Epidemiologic Research on Emerging Risk Factors and Liver Cancer Susceptibility”, we propose the first translational study to investigate PFAS as novel risk factors for HCC by integrating population-based research with in vitro experiments. Leveraging comprehensive epidemiological data spanning over two decades and pre-diagnostic plasma samples in the Multiethnic Cohort Study (MEC), we aim to elucidate the impact of PFAS exposure on MASLD and HCC risks. Additionally, using in vitro experiments with 3D human liver spheroids, 2D HepG2 cell cultures, and various omics techniques we will explore the biological pathways linking PFAS exposure to liver steatosis and HCC development. To enhance precision, high-dimensional machine learning methods will be employed to construct risk profiles for HCC based on PFAS plasma concentrations, multi-omics data, and genetic factors, offering new insights into personalized prevention strategies. Our specific aims are: 1) to evaluate associations between individual PFAS and PFAS mixtures in pre-diagnostic plasma samples with MASLD and HCC risk and examine whether genetic predisposition modifies the associations; 2) to examine the biological pathways underlying PFAS-induced liver steatosis and HCC using in vitro studies and single-cell omics; 3) to construct precise risk profiles of HCC based on PFAS plasma concentrations, genetics and multi-omics data. By combining epidemiological, mechanistic, and bioinformatics analyses, this study will provide critical insights into the role of environmental chemicals in HCC development. Our findings will inform policies to minimize PFAS exposure, reduce the burden of HCC, and identify potential targets for prevention and intervention strategies. Project Number: 1R01CA300355-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: VERONICA SETIAWAN (+1 co-PI) | Institution: UNIVERSITY OF SOUTHERN CALIFORNIA, Los Angeles, CA | Award Amount: $681,676 | Activity Code: R01 | Study Section: Cancer and Hematologic Disorders Study Section[CHD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11296815