PM_2.5 exposure‐induced ferroptosis in neuronal cells via inhibiting ERK/CREB pathway

Abstract

PM 2.5 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 2.5 -induced neurotoxicity and ferroptosis is still unclear. The current study aims to investigate if ferroptosis is involved in neurotoxicity post PM 2.5 exposure and its underlying mechanism. The PM 2.5 -treated neuronal Neuro-2a (N2A) and SH-SY5Y cells were applied to the current study. The results showed that PM 2.5 significantly increased the neuronal cell death, yet the ferroptosis antagonist Ferrostain-1 (Fer-1) markedly decreased the cell death induced by PM 2.5 . Western blot further confirmed that ferroptosis was triggered post PM 2.5 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 2.5 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 2.5 treatment.The addition of ERK1/2 agonist post PM 2.5 treatment significantly inhibit ferroptosis via increasing the expression of GPX4. Taken together, the present study demonstrated that PM 2.5 -induced ferroptosis via inhibiting ERK/CREB pathway, and these findings will advance our knowledge of PM 2.5 -induced cytotoxicity in the nervous system.

Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

“…Wang et al have affirmed that CREB directly binds the promoter of GPX4 in H1299 cells via ChIP experiments [ 22 ]. Xiong et al demonstrated that PM2.5 exposure induces ferroptosis in neuronal cells by inhibiting CREB [ 40 ]. Chen et al indicated that the bioflavonoid galangin delivered its anti-ferroptosis effects by activating CREB in a hepatic ischemia‒reperfusion model [ 41 ].…”

Cell Death Pathways: The Variable Mechanisms Underlying Fine Particulate Matter-Induced Cytotoxicity

“… 77 In an another study, FPM exposure would lead to ferroptosis in neuronal cells by inhibiting the extracellular regulated protein kinases (ERK)/cAMP-response element binding protein (CREB) pathway. 78 …”

“…g ., As, Pb and Cd, could induce imbalances in redox systems, thereby causing ferroptosis . In an another study, FPM exposure would lead to ferroptosis in neuronal cells by inhibiting the extracellular regulated protein kinases (ERK)/cAMP-response element binding protein (CREB) pathway …”

RBM15 silencing promotes ferroptosis by regulating the TGF‐β/Smad2 pathway in lung cancer

“…9,10 Ferroptosis is triggered through the inactivation of antioxidant defenses by dependent cellular glutathione (GSH), resulting in the increase of toxic lipid reactive oxygen species. 11 Evidence has determined that the ferroptosis is involved in a variety of pathological injuries, such as nickel oxide nanoparticles-induced acute lung injury, 12 1,3-DCP-induced hepatocytes injury, 13 hexavalent chromium-induced testicular injury, 14 PM2.5-induced neurological injury, 15 and cadmium-induced neurological injury. 16 In addition, ferroptosis also participates the progression of various cancers, including nasopharyngeal carcinoma, 17 gastric cancer, 18 colorectal cancer, 19 glioblastoma, 20 acute myeloid leukemia, 21 and trastuzumab-resistant breast cancer.…”