Celecoxib as a potential treatment for hepatocellular carcinoma in populations exposed to high PFAS levels.

Per- and polyfluoroalkyl substances (PFAS), including perfluorooctane sulfonate and perfluorooctanoic acid, are associated with adverse human effects. However, few studies have assessed the effects of PFAS mixtures on hepatocellular carcinoma (HCC). In this study, we systematically investigated the effects and underlying mechanisms of PFAS mixtures on the proliferation, migration, and invasion of HCC cells (JHH-7 and Li-7) in vitro using a combination of biological techniques and high-coverage untargeted metabolomics. A six day exposure to a 5 μM PFAS mixture significantly enhanced the malignant progression of HCC in vitro. Metabolomic analysis identified the upregulation of prostaglandin E2 (PGE2) as a key factor associated with these effects. This hypothesis was further validated using celecoxib, a PGE2 inhibitor, which reduced PGE2 levels in HCC cells, consequently slowing their migration and invasion. Additionally, mice treated with celecoxib exhibited reduced tumor volumes compared with those treated with PFAS alone. These results suggest that PFAS exposure enhances HCC malignancy through the PI3K/AKT signaling pathway via increased PGE2 production. In conclusion, a 5 μM PFAS mixture accelerates HCC proliferation and invasion; moreover, celecoxib demonstrates potential as a therapeutic agent that inhibits these effects.