1. BCAT1 alleviates early brain injury by inhibiting ferroptosis through PI3K/AKT/mTOR/GPX4 pathway after subarachnoid hemorrhage.
- Author
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Liu N, Li C, Yan C, Yan HC, Jin BX, Yang HR, Jiang GY, Gong HD, Li JY, Ma SJ, Liu HL, and Gao C
- Subjects
- Animals, Male, Mice, Rats, Chromones pharmacology, Disease Models, Animal, Lipid Peroxidation drug effects, Morpholines pharmacology, Neurons metabolism, Neurons pathology, Neurons drug effects, Rats, Sprague-Dawley, Brain Injuries metabolism, Brain Injuries pathology, Brain Injuries drug therapy, Brain Injuries etiology, Ferroptosis drug effects, Ferroptosis genetics, Phosphatidylinositol 3-Kinases metabolism, Phosphatidylinositol 3-Kinases genetics, Phospholipid Hydroperoxide Glutathione Peroxidase metabolism, Phospholipid Hydroperoxide Glutathione Peroxidase genetics, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-akt genetics, Signal Transduction, Subarachnoid Hemorrhage pathology, Subarachnoid Hemorrhage metabolism, Subarachnoid Hemorrhage drug therapy, Subarachnoid Hemorrhage genetics, TOR Serine-Threonine Kinases metabolism, TOR Serine-Threonine Kinases genetics
- Abstract
Regulation of the redox system by branched-chain amino acid transferase 1 (BCAT1) is of great significance in the occurrence and development of diseases, but the relationship between BCAT1 and subarachnoid hemorrhage (SAH) is still unknown. Ferroptosis, featured by iron-dependent lipid peroxidation accompanied by the depletion of glutathione peroxidase 4 (GPX4), has been implicated in the pathological process of early brain injury after subarachnoid hemorrhage. This study established SAH model by endovascular perforation and adding oxyhemoglobin (Hb) to HT22 cells and delved into the mechanism of BCAT1 in SAH-induced ferroptotic neuronal cell death. It was found that SAH-induced neuronal ferroptosis could be inhibited by BCAT1 overexpression (OE) in rats and HT22 cells, and BCAT1 OE alleviated neurological deficits and cognitive dysfunction in rats after SAH. In addition, the effect of BCAT1 could be reversed by the Ly294002, a specific inhibitor of the PI3K pathway. In summary, our present study indicated that BCAT1 OE alleviated early brain injury EBI after SAH by inhibiting neuron ferroptosis via activation of PI3K/AKT/mTOR pathway and the elevation of GPX4. These results suggested that BCAT1 was a promising therapeutic target for subarachnoid hemorrhage., Competing Interests: Declaration of competing interest All of the contributing authors declared no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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