Cigarette smoke extract induces ferroptosis in human retinal pigment epithelial cells in Age-related macular degeneration

Abstract Age-related macular degeneration (AMD) is one of the three major blindness diseases. Retinal pigment epithelium (RPE) dysfunction due to smoking is an essential environmental factor in the pathogenesis of AMD. Ferroptosis is a novel type of iron-dependent programmed cell death (PCD). However, the relationship between cigarette smoke extract (CSE)-induced RPE damage and ferroptosis remains unclear. In this study, we observed that CSE induced cellular damage in a human retinal pigment epithelial cell line (ARPE-19), resulting in ferrous ion (Fe2+) accumulation, an increas in reactive oxygen species (ROS) and lipid peroxidation (LP), a reduction in GSH levels, and the inhibition of Gpx4 expression. In addition, transmission electron microscopy (TEM) of in vivo and in vitro samples showed that after exposure to CSE, the mitochondria of RPE cells were wrinkled, the membrane density was increased, and the number of cristae decreased or cristae were not observed. Additionally, RPE cells were protected from damage by the ferroptosis inhibitors ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1). The findings of this study suggest that CSE can lead to RPE cell ferroptosis, which is associated with the pathogenesis of AMD.