Research Progress on the Application of PI3K/AKT Pathway in the Treatment of Depression

Authors

  • Kezhou Li

DOI:

https://doi.org/10.61173/8z027k87

Keywords:

depression, PI3K/AKT, BDNF

Abstract

Depression, also known as depressive disorder, is a common psychological disorder. The phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) signaling pathway can affect neurophysiological processes directly related to depression, such as synaptic transmission and neuroinflammatory response, by regulating downstream key molecules. This article explores the impact of the PI3K/ AKT pathway on depression. Through comprehensive literature analysis, this article shows the main molecular mechanisms of the PI3K/AKT signaling pathway and emphasizes the regulatory role of this pathway in synaptic plasticity, neuroinflammation, and dopamine expression, which directly affect depression. By consulting the recent progress in the development of medicines for depression and figuring out the underlying mechanism, this article concludes that medicines based on the PI3K/AKT pathway have great potential. If the potential safety issues can be addressed and the efficacy of the medicine treatment can be further improved, depression patients worldwide could be largely cured with medicines that modulate the PI3K/AKT pathway.

References

[1] Harry Costello, Jonathan P Roiser, Robert Howard. Antidepressant medications in dementia: evidence and potential mechanisms of treatment-resistance. Psychological Medicine, 2023, 53(3): 654-667.

[2] Numakawa T, Yokomaku D, Richards M, Hori H, Adachi N, Kunugi H. Functional interactions between steroid hormones and neurotrophin BDNF. World Journal of Biological Chemistry, 2010, 1(5): 133-143.

[3] Shouhei Miyazaki, Yoshio Fujita, Hirotaka Oikawa, Hideo Takekoshi, Hideaki Soya, Masato Ogata, Takahiko Fujikawa. Combination of syringaresinol–di–O–β-d-glucoside and chlorogenic acid shows behavioral pharmacological anxiolytic activity and activation of hippocampal BDNF–TrkB signaling. Scientific Reports, 2020, 10(1).

[4] Yan He, Miaomiao Sun, Guogeng Zhang, Jing Yang, Kuisheng Chen, Wenwen Xu, Bin Li. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduction and Target Therapy, 2021, 6(1): 425.

[5] Jichao Sun, Mo Chen. Navigating AKT-ivity across cellular compartments. Trends Cell Biology, 2025.

[6] Wenyan Cui,Yuping Ning, Wu Hong, Ju Wang Zhening Liu, Ming D. Li. Crosstalk Between Inflammation and Glutamate System in Depression: Signaling Pathway and Molecular Dean&Francis Kezhou Li Biomarkers for Ketamine’s Antidepressant Effect. Molecular Neurobiology, 2019, 56(5): 3484-3500.

[7] Ningning Guo, Xin Wang, Muran Xu, Jie Bai, Hao Yu, Le Zhang. PI3K/AKT signaling pathway: Molecular mechanisms and therapeutic potential in depression. Pharmacological Research, 2024, 206.

[8] Aisha Alhaddad, Asmaa Radwan, Noha A Mohamed, Eman T Mehanna, Yasser M Mostafa, Norhan M El-Sayed, Shaimaa A Fattah. Rosiglitazone Mitigates Dexamethasone-Induced Depression in Mice via Modulating Brain Glucose Metabolism and AMPK/mTOR Signaling Pathway. Biomedicines, 2023, 11(3): 860.

[9] MacRae F Linton, Javid J Moslehi, Vladimir R Babaev. Akt Signaling in Macrophage Polarization, Survival, and Atherosclerosis. International Journal of Molecular Sciences , 2019, 20(11): 2703.

[10] Wenfeng Hu, Jingjing Wu, Ting Ye, Zhuo Chen, Jinhua Tao, Lijuan Tong, Kai Ma, Jie Wen, Hui Wang, Chao Huang. Farnesoid X Receptor-Mediated Cytoplasmic Translocation of CRTC2 Disrupts CREB-BDNF Signaling in Hippocampal CA1 and Leads to the Development of Depression-Like Behaviors in Mice. International Journal of Neuropsychopharmacology, 2020, 23(10): 673-686.

[11] Z Zack Ma, Natalie J Guzikowski, Ji-Woon Kim, Ege T Kavalali, Lisa M Monteggia. Enhanced ERK activity extends ketamine’s antidepressant effects by augmenting synaptic plasticity. Science, 2025, 388(6747): 646-655.

[12] Panos Zanos, Ruin Moaddel, Patrick J Morris, Lace M Riggs, Jaclyn N Highland, Polymnia Georgiou, Edna F R Pereira, Edson X Albuquerque, Craig J Thomas, Carlos A Zarate Jr, Todd D Gould. Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacological Reviews, 2018, 70(3): 621-660.

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Published

2026-02-28