Abstract: Chronic stress is a major public health concern, contributing to a spectrum of physiological and psychological disorders, including anxiety, depression, cardiovascular diseases, and metabolic syndromes. This review examines the epigenetic mechanisms mediating the impact of chronic stress on human health, focusing on DNA methylation, histone modifications, and non-coding RNAs. These epigenetic alterations act as dynamic interfaces between environmental stressors and genomic responses, modifying gene expression in critical stress-related pathways, such as the hypothalamic- pituitary-adrenal (HPA) axis and neurotrophic factors like BDNF. The significance of this research lies in elucidating how these epigenetic changes, induced by early-life adversity, socioeconomic pressures, and environmental toxins, create lasting molecular imprints that increase susceptibility to stress-related disorders and can be transmitted across generations. Key findings include stress-induced hypermethylation of the glucocorticoid receptor gene (NR3C1), histone acetylation changes in brain regions like the hippocampus and amygdala, and the regulatory roles of microRNAs (e.g., miR-132) and long non-coding RNAs (e.g., HOTAIR). These modifications disrupt neural plasticity, emotional regulation, and cognitive function, while also contributing to physical health outcomes, including inflammation, metabolic dysregulation, and cancer. The review also explores therapeutic interventions, such as DNA methylation inhibitors (e.g., 5-azacytidine), histone deacetylase inhibitors (HDACIs), and lifestyle modifications like mindfulness and dietary polyphenols. By integrating molecular insights with clinical perspectives, this article underscores the critical role of epigenetic research in developing targeted interventions to mitigate the enduring effects of chronic stress, offering transformative potential for personalized medicine and public health strategies.
Abbas et al. (2026) studied this question.