Jet lag-induced circadian disruption elevates glioma risk by altering molecular profiles in distinct brain regions.

PURPOSE: To investigate the mechanism underlying chronic jet lag (CJL)-induced circadian disruption stimulating glioma-related gene expression across distinct brain regions, and to examine the regulatory role of core clock genes in modulating neural oncogenic susceptibility. METHODS: This experiment was initiated with the establishment of an animal model of CJL (6-h light-cycle advances every 2 days for 10 or 30 days) in wild-type and clock gene-deficient mice (Bmal1(-/-), Per1/2(-/-), and Cry1/2(-/-)). Then, tissues harvested from six neural regions (i.e., hippocampus, prefrontal cortex, striatum, hypothalamus, raphe nuclei, and nucleus accumbens) were subjected to tissue-specific qPCR profiling of cancer-related genes (C-MYC, MDM-2, GADD45A, and p53). Additionally, bioinformatics analyses (DAVID, ConsensusPathDB) was employed to identify pathway interactions, with statistical validation using ANOVA and t-tests. RESULTS: CJL induced brain region-specific dysregulation of oncogenic pathways, with marked activation of oncogenes (C-MYC↑, and MDM-2↑) in hypothalamic and striatal regions, while suppression of tumor suppressors (GADD45A↓, and p53↓) in hippocampal and cortical regions. Clock gene mutations amplified these effects, particularly in Bmal1(-/-) mice, indicating core clock components as critical modulators of neural oncogenesis. Meanwhile, sex-dependent differences emerged in cerebellar tumor suppressor responses to CJL. Besides, pathway analysis revealed circadian-glioma crosstalk through p53-mediated apoptosis and cell cycle regulation. CONCLUSION: Chronic circadian disruption acts as a brain region-specific oncogenic stressor, driving transcriptional reprogramming of cancer pathways in a clock gene-dependent manner. Mechanistically, our study may establish a relationship of circadian dysfunction with glioma risk, underscoring the necessity for sex-stratified chronotherapeutic approaches in neuro-oncology.