PM_2.5 induces autophagy-dependent ferroptosis by endoplasmic reticulum stress in SH-SY5Y cells

Fine particulate matter (PM_2.5 ) has been a global environmental problem threatening public health in recent years. PM_2.5 exposure was associated with an increased risk of neurodegenerative diseases related to neuronal apoptosis. Ferroptosis is a nonapoptotic form of programmed the cell death, characterized by excess iron-dependent lipid peroxidation products. Whether PM_2.5 could induce ferroptosis in cells and thus be involved in its neurotoxicity is unknown. In this study, we found that PM_2.5 induced endoplasmic reticulum stress, apoptosis, autophagy, and ferroptosis in neuroblastoma human neuroblastoma cells (SH-SY5Y). Interestingly, ferroptosis was the predominant form of mortality in the presence of high doses of PM_2.5 exposure. In addition, the endoplasmic reticulum stress inhibitor 4-phenylbutyric acid (4-PBA) inhibited PM_2.5 -induced cellular autophagy, apoptosis, and ferroptosis. Autophagy inhibitors chloroquine (CQ) alleviated PM_2.5 -induced ferroptosis but did not reverse apoptosis. We also found that inhibition of both endoplasmic reticulum stress and autophagy reversed the PM_2.5 -induced increase in the expression level of cytophagy nuclear receptor coactivator 4 (NCOA4). Our results suggested that PM_2.5 -induced ferroptosis in SH-SY5Y cells was autophagy-dependent ferroptosis due to endoplasmic reticulum stress, which might be associated with the elevation of iron content caused by NCOA4-mediated ferritin autophagy.