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Hippocampal REDD1 inhibition is critical for alleviating depressive-like behaviors

Acta Pharmacologica Sinica (2026) Cite this article

Abstract

Depression is characterized by distinct pathological and synaptic abnormalities in the hippocampus; however, the underlying mechanisms remain poorly understood. We demonstrate for the first time that Regulated in development and DNA damage response-1 (REDD1) is upregulated in hippocampal neurons in three depression models induced by typical stressors. Notably, the hippocampus is the only brain region where REDD1 is highly expressed—this effect is not observed in the hypothalamus, prefrontal cortex, nucleus accumbens, or dorsal raphe. Downregulation of REDD1 effectively rescued depressive-like behaviors in chronic social defeat stress (CSDS) model mice, activated mTORC1 in hippocampal neurons, and reduced synaptic loss, while overexpression of REDD1 specifically in hippocampal neurons triggered depressive-like behaviors in non-stressed mice. These findings were further validated using REDD1 knockdown and mTORC1 inhibition models. Moreover, a novel compound, X837, potently inhibited REDD1, leading to rapid alleviation of depression-like behaviors, robust activation of the mTORC1 pathway, and restoration of synaptic deficits. The antidepressant effects of X837 were dependent on the REDD1/mTORC1 axis in hippocampal neurons. In conclusion, REDD1 in hippocampal neurons is a potent antidepressant target which functions via the mTORC1 signaling pathway.

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Interfering with REDD1 is a potential target to rescue depressive-like behaviors.

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Fig. 1: Bioinformatic analysis via RNA-sequencing identified Redd1 in hippocampal neurons as a pivotal gene in CSDS model animals.
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Fig. 2: REDD1 knockdown in hippocampal neurons produced significant antidepressant-like effects via mTORC1 signaling.
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Fig. 3: Genetic overexpression of REDD1 in hippocampal neurons induced depression-like behaviors.
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Fig. 4: X837 inhibits the expression of REDD1 and exerts antidepressant effects.
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Fig. 5: X837 improved synaptic loss in hippocampal neurons via the REDD1/mTORC1 axis.
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Fig. 6: The effect of X837 on improving depression was abolished by rapamycin.
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Acknowledgements

This study was supported by the National Key Special Project of Science and Technology for Innovation Drugs of China (2017ZX09301013), Leading Technology Foundation Research Project of Jiangsu Province (BK20192005, China), and CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-5-011, China). The authors would like to thank the sharing platform for the use of large-scale experimental apparatuses at the State Key Laboratory of National Medicines, China Pharmaceutical University.

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Authors and Affiliations

  1. Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China

    Chen Xu, Meng-xing Liao, Shi-ze Zhang, Lai-xin-yue Shu, Yu-ang Chen, Meng-qin Wang, Tian Cheng, Xu-le Yang, Yuan Xie, Guang-ji Wang & Ji-ye Aa

  2. College of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China

    Chen Xu

  3. Key Laboratory of Drug Monitoring and Control, Drug Intelligence and Forensic Center, Ministry of Public Security, Beijing, 100193, China

    Peng Xu

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Contributions

CX, MXL, SZZ, XLY and LXYS performed experiments and collected data. YAC, MQW, and TC analyzed data. CX drafted the manuscript. PX provided ketamine and supervised the administration. YX, GJW, and JYA conceived the scientific ideas, supervised research, designed the experiments and refined the manuscript. All authors were involved in writing the paper and had final approval of the submitted and published version.

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Correspondence to Yuan Xie, Guang-ji Wang or Ji-ye Aa.

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The corresponding author Guang-ji Wang is a member of the Editorial Board of the journal Acta Pharmacologica Sinica, but he has not been involved in the peer-review or decision-making process for this manuscript.

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Xu, C., Liao, Mx., Zhang, Sz. et al. Hippocampal REDD1 inhibition is critical for alleviating depressive-like behaviors. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-026-01760-6

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