PM exposure-induced ferroptosis in neuronal cells via inhibiting ERK/CREB pathway.

PM exposure has been demonstrated to correlate with neurological disorders recently. Ferroptosis is recognized as a newly found programmed form of cell death associated with neurodegenerative diseases, while glutathione peroxidase 4 (GPX4) is a key regulator of ferroptosis. However, the relationship between PM -induced neurotoxicity and ferroptosis is still unclear. The current study aims to investigate if ferroptosis is involved in neurotoxicity post PM exposure and its underlying mechanism. The PM -treated neuronal Neuro-2a (N2A) and SH-SY5Y cells were applied to the current study. The results showed that PM significantly increased the neuronal cell death, yet the ferroptosis antagonist Ferrostain-1 (Fer-1) markedly decreased the cell death induced by PM . Western blot further confirmed that ferroptosis was triggered post PM treatment in N2A cells by decreasing expressions of GPX4 and ferritin heavy chain (FTH), as well as enhancing expressions of ferritin light chain (FTL) and transferrin receptor protein (TFRC). Meanwhile, PM treatment augmented neuronal oxidative damage and mitochondrial dysfunction. The bioinformatic analysis indicated that CREB could be the regulator of GPX4, and our results showed that ERK/CREB pathway was down-regulated in N2A cells post PM treatment. The addition of ERK1/2 agonist post PM treatment significantly inhibit ferroptosis via increasing the expression of GPX4. Taken together, the present study demonstrated that PM -induced ferroptosis via inhibiting ERK/CREB pathway, and these findings will advance our knowledge of PM -induced cytotoxicity in the nervous system.