Acute hypoxia suppresses blood glycolysis in saker falcons ( Falco cherrug) via NR3C1-mediated repression of HK1: Evidence from hematological and epigenomic profiling.

Ongoing climate change is driving high-altitude bird species to occupy even higher elevations, yet physiological and regulatory responses enabling these transitions remain poorly understood. This study investigated acute hypoxic responses in saker falcons ( Falco cherrug) inhabiting the Qinghai-Xizang Plateau by exposing individuals to simulated altitudes of 5 000-6 000 m above sea level (a.s.l.), exceeding their typical elevation range (approximately 4 300 m a.s.l.). GPS tracking data indicated that juvenile falcons maintained comparable activity levels across 4 000-5 000 m and 5 000-6 000 m a.s.l. ranges. However, pre-fledging individuals subjected to 6 000 m hypoxia for three days exhibited marked increases in hemoglobin concentration and blood glucose. Transcriptomic profiling revealed significant suppression of glycolytic activity, notably characterized by reduced expression of hexokinase 1 ( HK1), a key enzymatic gene involved in the glycolytic pathway. ATAC-seq further identified enhanced chromatin accessibility within the HK1 locus under hypoxia, revealing two conserved cis-regulatory elements recognized by the transcription factor NR3C1 in the hypoxia-treated group. NR3C1 expression was negatively correlated with HK1. Notably, both elements were unique and evolutionarily conserved in avian taxa, suggesting a potential role in hypoxia resilience among highland birds. These findings provide mechanistic insights into the molecular and physiological strategies employed by sakers to tolerate acute hypoxic stress and inform conservation efforts for high-altitude bird species on the Qinghai-Xizang Plateau and other alpine ecosystems facing accelerating climate change.