PM is an important risk factor for the development and progression of cognitive impairment-related diseases. Ferroptosis, a new form of cell death driven by iron overload and lipid peroxidation, is proposed to have significant implications. To verify the possible role of ferroptosis in PM-induced neurotoxicity, we investigated the cytotoxicity, intracellular iron content, iron metabolism-related genes, oxidative stress indices and indicators involving in Nrf2 and ferroptosis signaling pathways. Neurotoxicity biomarkers as well as the ferroptotic cell morphological changes were determined by Western Blot and TEM analysis. Our results revealed that PM induced cytotoxicity, lipid peroxidation, as indicated by MDA content, and neurotoxicity Aβ deposition in a dose-related manner. Decreased cell viability and excessive iron accumulation in HT-22 cells can be partially blocked by ferroptosis inhibitors. Interestingly, GPX activity, Nrf2, and its regulated ferroptotic-related proteins (i.e. GPX4 and HO-1) were significantly up-regulated by PM. Moreover, gene expression of , , and involved in iron homeostasis and NCOA4-dependent ferritinophagy were activated after PM exposure. The results demonstrated that PM triggered ferritinophagy-dependent ferroptotic cell death due to iron overload and redox imbalance. Activation of Nrf2 signaling pathways may confer a protective mechanism for PM-induced oxidative stress and ferroptosis.
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| http://dx.doi.org/10.1080/10934529.2024.2331938 | DOI Listing |
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