Transcriptomic profiling reveals immunometabolic gene regulation during a 24-h cold exposure survival simulation in...

Prolonged cold exposure imposes substantial physiological and operational demands; however, the molecular mechanisms supporting human adaptation to sustained cold remain poorly defined. In this first-in-human study, we conducted genome-wide transcriptomic profiling of peripheral blood leukocytes from eight healthy adult males during a 24-h whole body cold survival simulation (7.5°C). Blood samples were collected at four standardized time points to characterize the dynamics of gene expression during continuous cold stress. Despite the clear physiological strain, the global leukocyte transcriptome remained remarkably stable. Differential expression analyses revealed a focused, transient induction of immediate-early genes-including FOS, TAGAP, and TIPARP-primarily associated with standardized exercise bouts performed immediately before and after cold exposure, with expression returning to baseline thereafter. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment indicated activation of immune and stress response signaling pathways (e.g., Toll-like receptor, MAPK, and B-cell receptor signaling) following pre-cold exercise, whereas post-cold sampling was enriched for metabolic pathways, including oxidative phosphorylation and glycolysis/gluconeogenesis, consistent with sustained thermogenic demand and metabolic flexibility. Notably, prolonged cold exposure was not associated with broad inflammatory activation, suggesting that humans maintain transcriptomic homeostasis under sustained cold stress through targeted, energetically efficient immunometabolic regulation. These findings establish peripheral blood as a viable biosampling matrix for monitoring gene-environment interactions during prolonged cold exposure and demonstrate the feasibility of transcriptomic surveillance in extreme environments. Collectively, this study provides foundational systems-level insights into early molecular signatures of human cold resilience and informs the development of blood-based biomarkers, predictive models, and precision countermeasures to support health and performance in Arctic, military, and expeditionary settings.NEW & NOTEWORTHY This first-in-human study provides a systems-level characterization of leukocyte transcriptomic responses to 24-h continuous cold exposure. Despite clear physiological strain, the blood transcriptome remains remarkably stable, with only transient, targeted immunometabolic shifts. These findings reveal energy-efficient molecular homeostasis during sustained cold stress and establish peripheral blood transcriptomics as a viable platform for monitoring human cold adaptation in real-world and operational environments.