Xia Congyuan, Zuo Guoyan, Wang Manni, Wang Yuming, Guo Yuxuan, Han Yan, Xiang Honglin, Cheng Yungchi, Xu Jiekun, He Jun, Zhang Weiku
Institute of Clinical Medical Sciences & Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, P. R. China.
School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, P. R. China.
Mol Psychiatry. 2025 Mar 25. doi: 10.1038/s41380-025-02959-5.
Histidine triad nucleotide-binding protein 1 (HINT1) is related to depression. However, the underlying mechanisms and whether HINT1 is a therapeutic target for depression remain unclear. In this study, we report that loganin, an antidepressant candidate from our previous research, directly targets HINT1 to alleviate depressive-like behaviors. Overexpression of HINT1 in the hippocampus induces depressive-like behaviors. Mechanistically, HINT1 hinders sigma-1 receptor (Sigma-1R) binding to N-methyl-D-aspartate receptor (NMDAR), promotes postsynaptic density protein (PSD95) binding to NMDAR, inhibits brain derived neurotrophic factor (BDNF) signaling, and impairs synaptic plasticity. The interaction between HINT1 and NMDAR is disturbed by loganin. The antidepressant-like effects of loganin are reversed by HINT1 overexpression, Sigma-1R inhibitor and tropomyosin kinase receptor B (TrkB) inhibitor. These results not only indicate that HINT1 induces depression via impairing synaptic plasticity but also provide a candidate targeting HINT1 for depression therapy. Zhang et al. reported that a natural compound, loganin, improves synaptic plasticity and reduces depressive-like behaviors via its direct target HINT1. Mechanistically, overexpressed HINT1 hinders NMDAR/Sigma-1R interactions and increases NMDAR/PSD95 interactions, and HINT1/NMDAR interactions are disrupted by loganin treatment.
组氨酸三联体核苷酸结合蛋白1（HINT1）与抑郁症有关。然而，其潜在机制以及HINT1是否为抑郁症的治疗靶点仍不清楚。在本研究中，我们报告了莫诺苷（我们之前研究中的一种抗抑郁候选药物）直接作用于HINT1以减轻抑郁样行为。海马体中HINT1的过表达会诱发抑郁样行为。从机制上来说，HINT1会阻碍σ-1受体（Sigma-1R）与N-甲基-D-天冬氨酸受体（NMDAR）结合，促进突触后致密蛋白（PSD95）与NMDAR结合，抑制脑源性神经营养因子（BDNF）信号传导，并损害突触可塑性。莫诺苷会干扰HINT1与NMDAR之间的相互作用。HINT1过表达、Sigma-1R抑制剂和原肌球蛋白受体激酶B（TrkB）抑制剂可逆转莫诺苷的抗抑郁样作用。这些结果不仅表明HINT1通过损害突触可塑性诱导抑郁症，还为抑郁症治疗提供了一个靶向HINT1的候选药物。Zhang等人报告称，一种天然化合物莫诺苷通过其直接靶点HINT1改善突触可塑性并减少抑郁样行为。从机制上来说，过表达的HINT1会阻碍NMDAR/Sigma-1R相互作用并增加NMDAR/PSD95相互作用，而莫诺苷处理会破坏HINT1/NMDAR相互作用。
