Transcriptomic and epigenomic profiles analysis during human acclimatization to simulated high-altitude hypoxia

Hypobaric hypoxia (HH) induces coordinated physiological and molecular responses supporting acclimatization to reduced oxygen availability. However, the temporal integration of blood mRNA and miRNA expression during early HH exposure remains incompletely understood. Eight healthy males were exposed for 72 h to simulated moderate HH (~ 3500 m) in the terraXcube facility. Blood transcriptomic and miRNA profiles were analyzed at baseline and after 12, 24, and 72 h, together with physiological variables, reactive oxygen species (ROS), and circulating inflammatory and endothelial biomarkers. Differential expression analysis revealed a progression from early stress and innate immune responses at 12 h, involving FOSB , CITED4 , and IDO1 , to remodeling of lymphocyte-specific programs at 24 h, including PAX5 , TCF7 , and TNFRSF13C . At 72 h, broader changes involved AP-1 components ( JUN , JUNB , and FOSB ), lymphocyte regulators ( PAX5 and FOXP3 ), and the antioxidant gene SOD2 . Integrated analysis identified predicted miRNA–mRNA pairs displaying inverse expression patterns within these pathways. Notably, miR-486-3p was consistently upregulated and miR-29c-5p downregulated across all time points. Plasma biomarkers remained largely stable, except for a transient increase in ICAM-1 and a marked decrease in TNF-α at 12 h, while ROS increased early and subsequently stabilized. Together, these findings identify distinct but overlapping phases of early HH acclimatization, progressing from stress and innate immune activation to lymphocyte-specific and redox remodeling. The temporal dissociation between coordinated mRNA and miRNA expression changes and limited circulating inflammatory responses indicates that molecular adaptation extends beyond detectable systemic inflammatory activation.