Transcriptomic profiling and targeted validation reveal molecular mechanisms of oxygen therapy in high-altitude cerebral injury.

Overview

1. Department of Hyperbaric Oxygen, Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
2. School of Medicine, South China University of Technology, Guangzhou, China
3. Department of Orthopedics, Sixth Medical Center, Chinese PLA General Hospital, Beijing, China

Abstract

Background: Exposure to high-altitude hypoxia is associated with an increased risk of impaired brain structure and function, with oxidative stress and neuroinflammation widely recognized as key mechanisms involved. In this context, hyperbaric oxygen therapy is considered a potential intervention; however, the mechanism by which it affects cerebral function changes caused by high-altitude exposure remains to be further elucidated.

Objective: This study aims to explore and compare the therapeutic effects of normobaric oxygen (NBO) and hyperbaric oxygen (HBO) on high-altitude cerebral injury (HACI), and to elucidate the molecular mechanisms underlying their neuroprotective effects using transcriptomic profiling and targeted validation.

Methods: A mouse model of high-altitude cerebral injury was established using a hypobaric hypoxia chamber. Mice were exposed to a simulated altitude of 7,000 m (approximately 9.8% O₂ at 0.47 ATA) for 3 consecutive days to induce severe hypoxia. Animals were divided into four groups: Control (Con), High-Altitude exposure (HH), post-HH treated with normobaric oxygen (NBO; 100% O₂ at 1.0 ATA for 1 h daily for 3 days), and post-HH treated with hyperbaric oxygen (HBO; 100% O₂ at 2.0 ATA for 1 h daily for 3 days). Brain tissues were analyzed using H&E staining, RNA sequencing (RNA-seq), Western blotting for key pathway proteins, immunofluorescence for glial cell activation, and ELISA for inflammatory cytokines. Oxidative stress markers (SOD, MDA, GSH, NO) were also assessed.

Results: Histopathological analysis confirmed cerebral damage in the HH group, which was significantly ameliorated by both HBO and NBO treatments. RNA-seq revealed widespread disruption of the cerebral transcriptome following high-altitude exposure. Oxygen therapy was associated with partial restoration of global gene expression patterns. KEGG pathway analysis highlighted significant enrichment in pathways related to NF-κB signaling, cytokine–cytokine receptor interaction, IL-17 signaling, and PI3K–AKT signaling. Subsequent targeted validation demonstrated that oxygen treatment reduced oxidative stress (increased SOD and GSH; decreased MDA and NO) and modulated the PI3K–AKT signaling pathway (increased p-AKT/AKT). Concurrently, oxygen therapy attenuated neuroinflammatory responses, inhibiting microglial and astrocytic activation, reducing pro-inflammatory cytokine levels (IL-1β, IL-6, TNF-α), and modulating the TLR4–NF-κB signaling axis (decreased TLR4 and p-p65/p65). HBO treatment was associated with broader modulation of several molecular pathways involved in oxidative stress and inflammation.

Conclusion: Existing evidence suggests that HBO may exert protective effects against altitude-related brain injury. This mechanism likely involves activating the PI3K–AKT/Nrf2 axis to alleviate oxidative stress and inhibiting the TLR4–NF-κB pathway to reduce neuroinflammation, thereby partially restoring transcriptional homeostasis. However, the causal relationships between these pathways and their interactions require further validation and refinement.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• bioproject:PRJNA1447108, at NCBI BioProject; found in “Data availability statement”

Data availability statement

The raw RNA-seq data generated in this study have been deposited in the NCBI Sequence Read Archive (SRA, submission ID: SUB16095504) and are associated with the BioProject: PRJNA1447108. The public URL for the project is: https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1447108.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 4 authors, 7 keywords, 38 references.

Cite

This paper

Hu, X., Bai, X., Pan, S., & Li, H. (2026). Transcriptomic profiling and targeted validation reveal molecular mechanisms of oxygen therapy in high-altitude cerebral injury. Frontiers in neuroscience, 20, 1738756. https://doi.org/10.3389/fnins.2026.1738756

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