Assessing the Carcinogenic Potential of PFOA: A Molecular Network Approach to Liver Toxicity

ABSTRACT Perfluorooctanoic acid (PFOA), a prototypical per‐ and polyfluoroalkyl substance (PFAS), is widely used in industrial and consumer products but is classified as a Group 1 carcinogen by the IARC due to its environmental persistence and bioaccumulation. PFOA primarily targets the liver, inducing stress responses and mitochondrial‐mediated apoptosis, while promoting hepatoma cell proliferation through the mTOR pathway. To investigate the molecular mechanisms of PFOA‐induced liver cancer (LIHC), we will use a network toxicology approach that integrates multi‐omics data to construct a compound–target–disease network, focusing on potential targets like ALDH1B1, which encodes the aldehyde dehydrogenase family in the major pathway of alcohol metabolism. It is hypothesized that hepatic metabolic homeostasis is disrupted and hepatocellular carcinogenesis is ultimately promoted by PFOA through direct binding to ALDH1B1 and interference with its function. To confirm this, we will employ molecular docking and dynamics simulations to validate the binding interactions and toxicity mechanisms at the molecular level. This research aims to provide a comprehensive understanding of PFOA's hepatotoxicity and carcinogenicity while identifying potential targets for risk assessment and intervention strategies related to environmental exposure.