Multilayered regulation of BDNF DNA methylation in PTSD: a review from molecular mechanisms to trans generational inheritance

Post-traumatic stress disorder (PTSD) is a chronic psychiatric disorder triggered by a traumatic event. Its core features include intrusive flashbacks, persistent avoidance, negative cognition and mood changes, and heightened arousal. The global lifetime prevalence is approximately 3.9%, exceeding 5.0% in high-income countries and high-trauma-exposed populations. With rising incidence of natural disasters, violent conflicts, and public health incidents worldwide, PTSD has become a serious public health issue threatening people's mental health. However, its pathogenesis remains largely unknown, specific clinical diagnostic biomarkers are lacking, and treatment efficacy varies significantly across individuals. Molecular understanding of its pathophysiology is urgently needed. Brain-derived neurotrophic factor (BDNF), a key neurotrophic factor in the central nervous system, is crucial for regulating neuronal survival, differentiation, and synaptic plasticity. Abnormal synaptic plasticity is closely associated with abnormal fear memory storage and emotional regulation impairments in PTSD patients. DNA methylation, a classic epigenetic regulatory mechanism, can inhibit transcriptional activity by modifying CpG sites in gene promoter regions. Its role in regulating BDNF gene expression has been widely demonstrated. In recent years, more epidemiological and animal studies suggest that BDNF DNA methylation may serve as a key molecular bridge between trauma exposure and the onset of PTSD. Abnormally elevated BDNF promoter methylation levels have been detected in the peripheral blood and in core brain regions(hippocampu,samygdala) of PTSD patients. Furthermore, these methylation levels can predict the risk of developing PTSD after trauma and are significantly correlated with clinical features such as impaired cortisol secretion and generalized fear memory. This study conducted a literature review, with data collected from authoritative Chinese and English databases. Chinese literature was retrieved from CNKI (China National Knowledge Infrastructure) and Wan fang Data; English literature was sourced from PubMed and Web of Science. The search was restricted to articles published prior to December 2025, focusing on case-control studies investigating the association between BDNF DNA methylation and post-traumatic stress disorder (PTSD). This review followed a structured, but not systematic, search strategy. We focus on the specific molecular pathways by which BDNF DNA methylation contributes to PTSD pathogenesis by influencing neural circuit plasticity, hippocampal function, and hypothalamic-pituitary-adrenal (HPA) axis homeostasis. We also summarize its potential for application in the development of diagnostic biomarkers and targeted interventions for PTSD. We also outline cutting-edge research directions driven by emerging technologies such as single-cell sequencing and epigenetic editing. This article aims to provide theoretical references for a deeper understanding of the pathogenesis of PTSD and promote clinical translational research.