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

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.