FKBP51 mediates mitochondrial function via NF-κB pathway during sleep fragmentation-induced cognitive impairment

Yanbin Ji; Wenhao Chen; Luyan Yao; Fangfei Liu; Xiulian Sun; Zhong Wang

doi:10.1016/j.bbi.2026.106556

FKBP51 mediates mitochondrial function via NF-κB pathway during sleep fragmentation-induced cognitive impairment

Brain Behav Immun. 2026 Mar 25:136:106556. doi: 10.1016/j.bbi.2026.106556. Online ahead of print.

Authors

Yanbin Ji¹, Wenhao Chen², Luyan Yao³, Fangfei Liu⁴, Xiulian Sun⁵, Zhong Wang⁶

Affiliations

¹ Department of Neurology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China.
² Department of Psychiatry, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Key Laboratory of Precision Psychiatry, Hangzhou, China.
³ Department of Oncology Center, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, China.
⁴ Department of Neurology, Qilu Hospital of Shandong University, Jinan, China.
⁵ Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, China. Electronic address: xiulians@gmail.com.
⁶ Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China. Electronic address: wangzhong@bjmu.edu.cn.

PMID: 41895667
DOI: 10.1016/j.bbi.2026.106556

Abstract

Sleep disruption triggers neuroinflammation and cognitive deficits. While FKBP51 (FK506-binding protein 51) is a potential therapeutic target for stress-related psychiatric disorders, its role in sleep regulation remains unclear. Here, we show that sleep fragmentation (SF) impairs cognitive function and elevates serum levels of IL-1β, IL-6, and TNF-α, alongside increased hippocampal mRNA expression of these cytokines. Integrated transcriptomic and proteomics profiling revealed upregulation of Fkbp5 gene in the hippocampus of SF-exposed mice. Moreover, genetic knockout of Fkbp5 (Fkbp5^-/-) abolished SF-induced NF-κB pathway activation and the associated increase in mitochondrial p65 in the hippocampal dentate gyrus-effects consistently observed in wild-type mice. In vitro, LPS-induced mitochondrial dysfunction-manifested as impaired mitochondrial respiratory capacity, reduced ATP production, and elevated ROS generation-was significantly attenuated in Fkbp5-knockdown HT-22 cell lines. Crucially, SF induced the translocation of cytochrome c from the mitochondria to the cytosol, thereby initiating mitochondria-related apoptosis and amplifying the inflammatory response in WT mice; these effects were markedly reversed in Fkbp5^-/- mice. Notably, SAFit2 (a selective FKBP51 inhibitor) effectively suppressed NF-κB activation, restored mitochondrial function, and mitigated apoptosis and inflammation, consequently ameliorating cognitive deficits in SF-exposed mice. Our results demonstrate that FKBP51 downregulation alleviates SF-induced inflammation and cognitive impairment by inhibiting NF-κB signaling and preserving mitochondrial function. Pharmacological targeting of FKBP51 thus represents a promising strategy for counteracting SF-related inflammation and cognitive decline.

Keywords: Apoptosis; FKBP51; Inflammation; Mitochondria; NF-κB pathway; Sleep fragmentation.