Integrative transcriptomic, experimental, and Mendelian randomization evidence implicates CREB1 in chronic sleep...

Insomnia and anxiety frequently co-occur, but the molecular nodes linking sleep loss, inflammation, and affective dysregulation remain incompletely defined. Here, we integrated transcriptomic reanalysis, a rat chronic sleep deprivation (CSD) model, and Mendelian randomization (MR) to identify inflammation-related molecular candidates relevant to anxiety-like phenotypes. Public peripheral-blood datasets for insomnia and anxiety were intersected with inflammation-related genes, yielding 37 shared differentially expressed genes enriched in immune and inflammatory signaling. Protein-protein interaction analysis and qRT-PCR prioritized CREB1 and CXCR4 for experimental validation. In rats, CSD disrupted sleep architecture on EEG/EMG and induced anxiety-like behaviors in the open field and elevated plus maze. In the amygdala, CSD increased TNF-α, IL-6, CXCR4, Iba1, p-NF-κB p65/NF-κB p65, p-ERK1/2/ERK1/2, phosphorylated CREB1, and BDNF, whereas total CREB1 remained unchanged, consistent with microglial activation-related changes, NF-κB/ERK-linked inflammatory signaling, and CREB1/BDNF-related plasticity remodeling. Two-sample MR using eQTLGen and FinnGen data further supported CREB1, with genetically predicted higher CREB1 expression associated with increased anxiety-disorder risk (IVW OR = 1.28, 95% CI 1.06-1.54, p = 0.0089). CXCR4 could not be tested genetically because of insufficient instrumental variables. These convergent findings implicate CREB1 as a candidate molecular node linking neuroinflammatory signaling to anxiety-like phenotypes after chronic sleep deprivation, while CXCR4 may represent an experimentally supported upstream neuroimmune candidate requiring direct mechanistic validation.