NDRG2 as a Promising Therapeutic Target in Depression: A Review of its Multifaceted Mechanisms

Depression is a common mood disorder with limited treatment efficacy. N-myc downstream-regulated gene 2 (NDRG2) is a stress-responsive molecule expressed in astrocytes and has been recognized as a key regulator in depression; however, its underlying mechanisms remain largely unclear. This review summarizes the current evidence and highlights two important points. First, NDRG2 integrates multiple well-established depression-related pathways—including astrocyte apoptosis, neuroinflammation, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, synaptic plasticity, glutamate homeostasis, neurogenesis, mitochondrial dysfunction, and brain-blood barrier (BBB) dysfunction—into a coordinated regulatory network. Second, NDRG2 exhibits dual effects depending on the pathological context, suggesting that targeting it may offer a more precise therapeutic strategy than approaches that modulate single pathways. By proposing an NDRG2-centered network model for depression, this review provides a new conceptual framework for understanding the disease and positions NDRG2 as a promising yet challenging therapeutic target. Further studies are needed to clarify its precise molecular mechanisms and evaluate its translational potential.