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 <i>in vivo</i>. 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 <i>in vivo</i> and <i>in vitro</i>. However, ATF4 knockdown decreased ischemic foci and volume and restored sensory functions <i>in vivo</i>. ATF4 knockdown suppressed lipid peroxidation and neuronal ferroptosis <i>in vitro</i>. 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.