Jiayu Li, Xuchu Guan, Ruigang Zhang, Huahua Zhang
Abstract Major depressive disorder (MDD) is a widespread, recurrent, and severely disabling psychiatric disorder that imposes a heavy global health burden. Although genetic factors contribute to disease risk, growing evidence highlights gene-environment interaction as the core driver of MDD pathogenesis. Epigenetic regulation acts as a precisely molecular interface that translates environmental stressors into stable changes in gene expression and long-term behavioral phenotypes. In this review, we provide a comprehensive and up-to-date overview of epigenetic dysregulation in MDD, covering five major regulatory layers: DNA methylation, histone post-translational modifications, non-coding RNA networks, RNA chemical modifications, and ATP-dependent chromatin remodeling. We emphasize the spatiotemporal specificity, brain regional selectivity, and cell-type. dependency of these epigenetic events, and their roles in disrupting neuroplasticity, hypothalamic–pituitary–adrenal (HPA) axis function, neurotransmitter homeostasis, and neuroinflammation. We further evaluate the translational value of peripheral epigenetic markers for early diagnosis, severity monitoring, and prediction of antidepressant treatment responses. We also discuss emerging epigenetic-targeted therapeutic strategies, including small-molecule inhibitors, RNA-based modulators, and brain-targeted delivery systems. Finally, we address key obstacles to clinical translation, such as tissue heterogeneity, unclear causality, limited reproducibility, and lack of standardized protocols. We propose future directions centered on single-cell multi-omics, longitudinal clinical validation, and sex-and ethnicity-stratified research. This review aims to establish an integrated framework for understanding MDD epigenetics and accelerating the development of precision diagnostic and therapeutic approaches.