circFKBP8(5S,6)-encoded protein promotes stress susceptibility in mice by down-regulating dopamine D3 receptor expression and its downstream AMPK/mTOR/ULK1 autophagy signaling.

Dandan Xu, Zihan Huang, Gaojia Zhang, Jiao Jiao, Yujia Cao, Mengyu Liu, Yan Kong, Zhijun Zhang

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Article in Genes & diseases, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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8 authors.

Dandan XuDepartment of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Research Institution of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, Jiangsu 210009, China.

Zihan HuangDepartment of Biochemistry and Molecular Biology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.

Gaojia ZhangDepartment of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Research Institution of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, Jiangsu 210009, China.

Jiao JiaoDepartment of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Research Institution of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, Jiangsu 210009, China.

Yujia CaoDepartment of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Research Institution of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, Jiangsu 210009, China.

Mengyu LiuDepartment of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Research Institution of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, Jiangsu 210009, China.

Yan KongDepartment of Biochemistry and Molecular Biology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China.

Zhijun ZhangDepartment of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Research Institution of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, Jiangsu 210009, China.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Major depressive disorder (MDD) is a serious mental disorder, yet the mechanism by which circular RNAs (circRNAs) are involved in the pathogenesis of MDD by encoding proteins is unknown. Our previous study has shown that circFKBP8(5S,6) relies on its encoded protein, namely cFKBP8, to promote susceptibility to chronic unpredictable mild stress (CUMS) in mice, but the precise molecular mechanisms are unknown. Here we found that overexpression of circFKBP8(5S,6) or cFKBP8 in neurons of the prelimbic cortex (PrL) of CUMS mice down-regulated the expression levels of DRD3 and its downstream AMPK/ULK1 (Ser555) and AMPK/mTOR/ULK1 (Ser757) pathways, which resulted in down-regulation of neuronal autophagy levels. Interestingly, both the activation and overexpression of DRD3 ameliorated the exacerbation of depressive-like behaviors induced by circFKBP8(5S,6) or cFKBP8, activated both the AMPK/ULK1 (Ser555) pathway and the AMPK/mTOR/ULK1 (Ser757) pathway, and up-regulated neuronal autophagy levels. In conclusion, circFKBP8(5S,6) or cFKBP8 promotes susceptibility to CUMS in mice, at least in part, by down-regulating DRD3 expression and its downstream AMPK/mTOR/ULK1 signaling pathway-mediated neuronal autophagy.

Indexed as

AutophagycircRNA-encoded proteincircRNAsDopamine D3 receptorMajor depressive disorder

Identifiers

PMID41459113

DOI10.1016/j.gendis.2025.101718

PMCPMC12741372

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