The role of zinc homeostasis in major depressive disorder: heterogeneous pathological mechanisms and therapeutic implications

BACKGROUND: Major depressive disorder (MDD) involves multifaceted pathologies including neurotransmission, neuroplasticity, inflammation, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. Growing evidence implicates zinc homeostasis imbalance in MDD, yet a systematic framework integrating it into these mechanisms is lacking. METHODS: This narrative review synthesizes literature (2000-2024) to elucidate the multidimensional associations between zinc homeostasis and MDD pathology, focusing on zinc's roles in neurotransmitter regulation, BDNF signaling, inflammation, oxidative stress, and HPA axis activity. RESULTS: Epidemiological studies indicate an inverse correlation between serum zinc levels and MDD. Mechanistically, zinc imbalance may disrupt neural signaling via glutamate/GABA/5-HT receptors, impair neurotrophy via BDNF, exacerbate neuroinflammation and oxidative stress, and promote HPA axis hyperactivity. Zinc supplementation shows efficacy in mild-to-moderate MDD and augments conventional antidepressants, especially in treatment-resistant cases. Novel targets like GPR39 and zinc transporters, along with brain-targeted formulations, offer promising therapeutic avenues. CONCLUSIONS: Zinc homeostasis is critically involved in MDD's heterogeneous pathology, making it a promising target for precision treatment. However, this potential is tempered by inconsistent data and methodological limitations. Future research should prioritize: standardizing assessment methods; investigating brain region-specific zinc dynamics; developing novel targeted formulations; and exploring gene-environment interactions in zinc signaling.