2. Academic Validation
  3. Dual regulatory roles of CPT1C in chronic stress-induced depression-related outcomes

Dual regulatory roles of CPT1C in chronic stress-induced depression-related outcomes

  • Mol Psychiatry. 2026 Jul;31(7):3758-3774. doi: 10.1038/s41380-026-03516-4.
Dan Tian # 1,  Zhi-Xuan Xia # 2,  Si-Ying Wang # 1,  Ting Cao # 3,  Yue Pan 1,  Yue-Ling Zhao 1,  Ling Zheng 1,  Bing-Jie Wei 4,  Shao-Wei Yang 1,  Wei-Kai Chen 1,  Jie-Yan Zheng 5,  Zheng-Hua Su 1,  Zhou Chen 6,  Wu-Cheng Tao 7,  Yi-Xiao Luo 8,  Zhong-Meng Lai 9,  Hong Li 10,  Shuang-Qi Gao 11,  Hua Fan 12,  Zu-Cheng Shen 13 14
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, China.
  • 2 Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, 571199, China.
  • 3 Department of Children's Stomatology, Stomatological Hospital of Xiamen Medical College, Xiamen, 361003, China.
  • 4 The School of Nursing, Fujian Medical University, Fuzhou, 350122, China.
  • 5 Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
  • 6 Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, China.
  • 7 Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Medical University, Fuzhou, 350122, China.
  • 8 Hunan Province People's Hospital, The First-affiliated Hospital of Hunan Normal University, Changsha, 410002, China.
  • 9 Department of Anesthesiology, Union Hospital, Fujian Medical University, Fuzhou, 350001, China.
  • 10 The School of Nursing, Fujian Medical University, Fuzhou, 350122, China. [email protected].
  • 11 Department of Neurosurgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China. [email protected].
  • 12 Office of Research & Innovation, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471003, China. [email protected].
  • 13 Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, China. [email protected].
  • 14 Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Medical University, Fuzhou, 350122, China. [email protected].
  • # Contributed equally.
PMID: 41741705 DOI: 10.1038/s41380-026-03516-4
Abstract

Regulation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) function has emerged as a novel strategy for major depressive disorder (MDD); however, the underlying molecular mechanisms remain unclear. Here, we demonstrate that enhanced GluA1 depalmitoylation in the nucleus accumbens mediates depressive-like behaviors following chronic stress, and identify that the dysfunction of carnitine palmitoyltransferase 1 C (CPT1C), a depalmitoylating enzyme that specifically depalmitoylates GluA1, mediated depression-like behaviors in mice. Furthermore, dopamine D2 receptor-expressing medium spiny neurons (D2-MSN)-specific knockdown of CPT1C prevented stress-induced depression-like behaviors, and CPT1C deficiency in D1-MSN abolished the behavioral and synaptic plasticity alterations caused by fluoxetine treatment. More importantly, CPT1C is directly involved in regulating GluA1 synthesis through disinhibiting mTORC1 signaling by targeting tuberous sclerosis complex 2. Collectively, these results newly identify CPT1C as a dual regulator of GluA1 function from protein synthesis, post-translational modification to subcellular localization, and show that CPT1C may serve as a promising novel therapeutic target for MDD.

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