ATF4 Exacerbates Cerebral Infarction-Induced Sensory Dysfunction via HDAC1/DNMT1/GPX4 Signaling

Cerebral infarction is the main cause of death and long-term disability worldwide. Neuronal degeneration and limp sensory dysfunction are the secondary damages induced by cerebral infarction. This study aimed to investigate the roles of activating transcription factor 4 (ATF4) in cerebral infarction and the underlying molecular mechanisms. Middle cerebral artery occlusion (MCAO) surgery was applied to establish a cerebral infarction model in vivo. Histological analysis was performed using Nissl assay. Gene expression was determined using immunohistochemistry, immunofluorescence, and Western blot. Gene interaction was confirmed by co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and luciferase assays. Cellular functions were determined using Cell Counting Kit assay (CCK-8), propidium iodide (PI) staining, and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assays. ATF4 was overexpressed in cerebral infarction models in vivo and in vitro. However, ATF4 knockdown decreased ischemic foci and volume and restored sensory functions in vivo. ATF4 knockdown suppressed lipid peroxidation and neuronal ferroptosis in vitro. Moreover, ATF4 activated DNA methyltransferase 1 (DNMT1), which induced glutathione peroxidase 4 (GPX4) DNA methylation and decreased its expression. GPX4 knockdown alleviated the effects of shATF4 and promoted neuronal ferroptosis. Overall, ATF4 knockdown protected against cerebral infarction and sensory dysfunction by promoting DNMT1-mediated DNA methylation of GPX4.