Per- and polyfluoroalkyl substances exposure and risk of liver cancer: A comprehensive review of epidemiological and mechanistic evidence.

Per- and polyfluoroalkyl substances (PFASs), such as perfluorooctanoic acid and perfluorooctane sulfonic acid, are synthetic compounds that are persistent in the environment and widely used in industrial and consumer products. Their bioaccumulative potential and pervasive human exposure have raised serious concerns about hepatotoxicity and carcinogenicity. This review thoroughly examines current epidemiological and experimental evidence linking PFASs exposure to an increased risk of liver cancer, particularly hepatocellular carcinoma. Epidemiological studies show higher PFASs levels in hepatocellular carcinoma patients, with notable sex-specific associations suggesting hormonal influences. Mechanistic studies indicate that PFASs disrupt lipid and bile acid metabolism, induce oxidative stress, cause epigenetic alterations, and activate key oncogenic pathways including peroxisome proliferator-activated receptor α, PI3K/AKT/mTOR, and necroptosis inhibition. Together, these effects foster pro-tumorigenic microenvironment that promotes malignant transformation and proliferation. Despite growing evidence, significant knowledge gaps remain regarding PFASs effects on liver cancer, tumor immunity, and outcomes from mixed exposure. Future research should prioritize large-scale longitudinal studies, in-depth mechanistic investigations, and the development of targeted therapeutic and regulatory strategies to reduce PFASs-associated liver cancer risks.