Ferroptosis and Oxidative Stress Are Implicated Perfluorooctane Sulfonate-Elicited Cytotoxicity to Human Umbilical Vein Endothelial Cells.

Abstract

Perfluorooctane sulfonic acid (PFOS) is one of the per- and polyfluoroalkyl substances (PFASs) that increases the risk of developing cardiovascular diseases (CVDs) closely related to endothelial damage. Ferroptosis is a new form of cell death involving multiple metabolic pathways; the role of ferroptosis in endothelial damage by PFOS is unknown. To investigate whether oxidative stress and ferroptosis mediate PFOS-triggered endothelial injury, human umbilical vein endothelial cells (HUVECs) were exposed to PFOS with or without Fer-1 intervention. Cellular function was evaluated via cell viability and migration assays. Markers associated with oxidative stress and ferroptosis were quantitatively detected, and the expression of relevant proteins was further analyzed using Western blot and immunofluorescence staining. Exposure to PFOS led to elevated reactive oxygen species (ROS), Fe2+ accumulation, malondialdehyde (MDA) levels, and reduced glutathione (GSH) and glutathione peroxidase 4 (GPX4) expression. These changes were accompanied by impaired cell migration and alterations in endothelial function-related indicators and vasoactive mediators. Fer-1 intervention partially attenuated PFOS-induced impairment. Further mechanistic analysis showed that PFOS triggered ferroptosis through inhibiting the SLC7A11-GSH-GPX4 pathway and stimulating oxidative stress signal cascades.