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

Abstract

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.

Keywords: Zinc; heterogeneous pathological mechanisms; major depressive disorder; zinc homeostasis.

Figure 1.

Literature screening flow diagram.

Figure 2.

Schematic diagram of zinc homeostasis regulation mechanism [16]. This figure shows that Zrt- and Irt-like proteins (ZIP, blue) are responsible for transporting zinc ions into cells, zinc transporters (ZnT, orange) are responsible for transporting zinc ions out of cells, and metallothionein (MT, gray) acts as a buffer for zinc ions, binding or releasing zinc ions according to cellular needs, collectively maintaining intracellular zinc ion homeostasis. Adapted from Costa MI, et al. (2023), “Zinc: From Biological Functions to Therapeutic Potential”, *Int J Mol Sci*, Copyright © 2023 Costa MI, et al. Licensed under CC BY 4.0.

Figure 3.

Diagram of neuromodulator release and targets [205]. The figure shows that synaptic zinc is co-released with glutamate from small synaptic vesicles. Zinc allosterically modulates NMDA, AMPA, and GABA receptors, and also acts as a ligand for metabotropic zinc receptors (mZnR), demonstrating the important targets and modes of action of zinc in neuromodulation. Adapted from Bizup B, et al. “On the genesis and unique functions of zinc neuromodulation”, *Journal of Neurophysiology*, Copyright © 2024 the American Physiological Society. Licensed under CC BY 4.0.

Figure 4.

Diagram of postsynaptic effects of zinc signaling [220]. This figure shows the process by which synaptic zinc activates GPR39, induces PLC activation, and ultimately leads to an increase in intracellular Ca²⁺ concentration. Meanwhile, zinc also affects adenylate cyclase-mediated pathways by regulating 5-HT_1A and 5-HT₇ receptors, reflecting the important regulatory role of zinc in the 5-HT system. Adapted from Siodłak D, et al. “Interaction between zinc, the GPR39 zinc receptor and the serotonergic system in depression,” *Brain Res Bull*, Copyright © 2021 Elsevier Inc. Reused with permission, RightsLink License Number: 6087400108246.

Figure 5.

Diagram of GPR39 activation and BDNF pathway [100]. Zinc, as a natural ligand, activates metabotropic GPR39, triggering Gαs and Gαq signaling pathways. The activated GPR39 initiates a series of biochemical reactions, leading to CRE-dependent gene transcription and affecting the expression of CREB. Enhanced CREB expression can increase the expression of BDNF and TrkB. BDNF binds to TrkB receptors, directly participating in neurite growth, neuroplasticity, and phenotypic maturation. Adapted from Meng Y, et al. “The Changes of Blood and CSF Ion Levels in Depressed Patients: a Systematic Review and Meta-analysis,” *Mol Neurobiol*, Copyright © 2024, Yulu Meng et al. Reused with permission, RightsLink License Number 6087470573138.

Figure 6.

Schematic diagram of the interaction between Shank3 and synaptic zinc [256]. Shank3 is a zinc-responsive postsynaptic scaffolding protein containing multiple domains. It interacts with AMPA receptors, NMDA receptors, metabotropic glutamate receptors (mGluR), and the actin cytoskeleton through the N-terminal ankyrin repeat domain (ANK), Src homology 3 domain (SH3), PSD-95-Discs large-ZO-1 domain (PDZ), proline-rich fragment (Pro-rich), and C-terminal sterile α motif domain (SAM). The localization and oligomerization of Shank3 in the postsynaptic density (PSD) depend on the binding of zinc to the C-terminal SAM domain. Adapted from Ross MM, et al. “Neurodevelopmental Consequences of Dietary Zinc Deficiency: A Status Report”, *Biol Trace Elem Res*, Copyright © 2023 Ross MM, et al. Reused with permission, RightsLink License Number 6087470930069.

Figure 7.

Mechanism by which zinc inhibits LPS-induced inflammatory responses by upregulating zinc finger protein A20 [138]. Zinc binds to the zinc finger domain of A20 and promotes its expression. A20 inhibits the nuclear translocation of NF-κB through deubiquitination of key molecules in the NF-κB pathway (p65, IκB), thereby reducing the release of proinflammatory cytokines (TNFα, IL-6, COX-2, iNOS, etc.). Meanwhile, zinc can reduce the production of ROS and alleviate oxidative damage. This regulatory process can inhibit neuroinflammation caused by excessive activation of microglia, thereby alleviating inflammation-related depression-like behaviors. Adapted from Hongxia L, et al. “Zinc inhibited Lipopolysaccharide (LPS)-induced inflammatory responses by upregulating A20 expression in microglia BV2 cells”, *J Affect Disord*, Copyright © 2019 Elsevier B.V. Reused with permission, RightsLink License Number 6087410062583.

Figure 8.

Reveals the mechanism of the vicious cycle between post-stroke HPA axis hyperactivity and neuroinflammation [193]: As an intense stressor, stroke activates the HPA axis through two aspects—proinflammatory cytokines (IL-1, TNF-α, IL-6) released by brain injury directly stimulate the hypothalamus to secrete CRH, promoting the pituitary to release ACTH and the adrenal glands to secrete GCs; stroke lesions damage the HPA axis inhibitory regions in the frontal lobe/medial temporal lobe, and at the same time, the damaged hippocampus loses its feedback inhibitory effect, exacerbating excessive GCs secretion. In addition, GCs increase intestinal permeability, causing endotoxin translocation and peripheral inflammation, and activating microglia to release more inflammatory factors, forming a “neuroinflammation-HPA axis hyperactivity” cycle, which ultimately induces depression-like behaviors; zinc deficiency exacerbates this cycle, while zinc supplementation can alleviate hyperactivity by regulating HPA axis negative feedback. Adapted from Zhou L, et al. (2022), “The etiology of poststroke-depression: a hypothesis involving HPA axis”, *Biomed Pharmacother*, Copyright © 2022 Zhou L, et al. Licensed under CC BY-NC-ND.