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Post-traumatic stress disorder (PTSD) emerges in a subset of individuals following exposure to traumatic events and is characterized by marked variability in susceptibility and resilience. Epigenetic mechanisms, particularly DNA methylation, have been implicated in psychiatric disorders; however, their specific role in regulating stress-related genes in the context of PTSD remains insufficiently understood. This study investigated the epigenetic regulation of the metabotropic glutamate receptor 5 (mGluR5) gene in the hippocampus and its association with individual differences in PTSD vulnerability, utilizing the single prolonged stress (SPS) model. Rats were subjected to SPS, which included restraint, forced swimming, ether exposure, and electric foot shock, to induce PTSD-like phenotypes. Behavioral tests including the Forced Swimming Test, Sucrose Preference Test, Open Field Test, Elevated Plus Maze, and Light-Dark Chamber Test were used to stratify animals into Normal, High Susceptibility (HS), and Low Susceptibility (LS) groups. Molecular analyses revealed that the HS group exhibited significant downregulation of hippocampal mGluR5 mRNA expression and increased CpG methylation within the mGluR5 promoter region, whereas no such changes were observed in the LS group. Biochemically, the HS group showed elevated levels of corticotropin-releasing factor (CRF) in the paraventricular nucleus and increased serum corticosterone (CORT), indicating hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. Inflammatory analysis revealed increased levels of interleukin-1β (IL-1β) and reduced interleukin-10 (IL-10), along with enhanced expression of the microglial activation marker Iba-1. Oxidative stress was also pronounced in the HS group, as evidenced by increased malondialdehyde (MDA) and reduced levels of glutathione (GSH) and superoxide dismutase (SOD). These alterations were minimal or absent in the LS group. Collectively, these findings suggest that mGluR5 gene methylation in the hippocampus contributes to PTSD susceptibility by modulating gene expression in concert with neuroendocrine, inflammatory, and oxidative stress pathways. mGluR5 methylation may represent a promising biomarker for PTSD risk stratification and a potential target for epigenetic-based therapeutic intervention.