Perfluorooctane sulfonate mediates GSH degradation leading to oral keratinocytes ferroptosis and mucositis through activation of the ER stress-ATF4-CHAC1 axis

Abstract

Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant that induces inflammatory response and oxidative stress in oral mucosa. Ferroptosis, a form of cell death characterized by iron-dependent lipid peroxidation (the oxidative degradation of lipids), was believed to play a crucial role in pathogenesis of oral mucositis; however, the involvement of PFOS-induced ferroptosis remained unclear. Our findings demonstrated that PFOS inhibited proliferation and induced pro-apoptotic effects in oral cells, with the most pronounced effects observed in human oral keratinocytes (HOK). PFOS significantly increased reactive oxygen species (ROS) and lipid peroxidation, and depleted glutathione (GSH) in HOK cells. Notably, PFOS decreased glutathione peroxidase 4 (GPX4) expression and elevated Fe 2 + levels, suggesting a potential induction of ferroptosis. Ferroptosis inhibitors mitigated PFOS-induced lipid peroxidation and GSH depletion, subsequently enhancing cell viability. Mechanistically, PFOS-induced endoplasmic reticulum (ER) stress contributed to the increased expression and nuclear translocation (from the cytoplasm into the nucleus) of activating transcription factor 4 (ATF4) and up-regulated its downstream target gene Chac1 . Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) catalyzed the conversion of GSH into cysteinylglycine and 5-oxoproline, resulting in GSH depletion—a critical factor in PFOS-induced ferroptosis. Knocking down CHAC1 attenuated PFOS-induced ferroptosis. Tauroursodeoxycholic acid (TUDCA), the classical ER stress inhibitor, attenuated PFOS-induced oral keratinocytes ferroptosis and mucositis by inhibiting ATF4/CHAC1 pathway activation. These findings elucidated the toxicological mechanisms of PFOS and proposed potential therapeutic strategies to counteract PFOS exposure induced oral mucositis. • PFOS inhibits the viability of oral cells and promotes cell death. • PFOS exposure causes GSH depletion and induces cellular ferroptosis. • PFOS trigger ferroptosis by activating the ER stress-ATF4-CHAC1 axis. • TUDCA, a ER stress inhibitor, mitigates PFOS-induced oral keratinocytes ferroptosis and mucositis.

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