AimsIncidence of acute mountain sickness (AMS) ranges from 40%-90%, with high-altitude cerebral edema (HACE) representing a life-threatening end stage of severe AMS. However, practical and convenient preventive strategies for HACE are lacking. Remote ischemic preconditioning (RIPC) has demonstrated preventive effects on ischemia- or hypoxia-induced cardiovascular and cerebrovascular diseases. This study aimed to investigate the potential molecular mechanism of HACE and the application of RIPC in preventing HACE onset.MethodsA hypobaric hypoxia chamber was used to simulate a high-altitude environment of 7000 meters. Metabolomics and metabolic flux analysis were employed to assay metabolite levels. Transcriptomics and quantitative real-time PCR (q-PCR) were used to investigate gene expression levels. Immunofluorescence staining was performed on neurons to label cellular proteins. The fluorescent probes Mito-Dendra2, iATPSnFR1.0, and CMTMRos were used to observe mitochondria, ATP, and membrane potential in cultured neurons, respectively. TUNEL staining was performed to detect and quantify apoptotic cell death. Hematoxylin and eosin (H&E) staining was utilized to analyze pathological changes, such as tissue swelling in cerebral cortex samples. The Rotarod test was performed to assess motor coordination and balance in rats. Oxygen-glucose deprivation (OGD) of cultured cells was employed as an in vitro model to simulate the hypoxia and hypoglycemia induced by RIPC in animal experiments.ResultsWe revealed a causative perturbation of glucose metabolism in the brain preceding cerebral edema. Ischemic preconditioning treatment significantly reprograms glucose metabolism, ameliorating cell apoptosis and hypoxia-induced energy deprivation. Notably, ischemic preconditioning improves mitochondrial membrane potential and ATP production through enhanced glucose-coupled mitochondrial metabolism. In vivo studies confirm that RIPC alleviates cerebral edema, reduces cell apoptosis induced by high-altitude hypoxia, and improves motor dysfunction resulting from cerebral edema.ConclusionsOur study elucidates the metabolic basis of HACE pathogenesis. This study provides a new strategy for preventing HACE that RIPC reduces brain edema through reprogramming metabolism, highlighting the potential of targeting metabolic reprogramming for neuroprotective interventions in neurological diseases caused by ischemia or hypoxia. RIPC ameliorated brain edema induced by high-altitude hypoxia through stimulating glucose metabolism down to the TCA cycle to boost mitochondrial ATP production. This finding supports the potential of RIPC as a viable therapeutic approach for the prevention and treatment of HACE, targeting metabolic reprogramming. This figure was created with BioRender ().image