High-altitude hypoxia aggravated neurological deficits in mice induced by traumatic brain injury via BACH1 mediating astrocytic ferroptosis

作者：Peng Zou, Tianjing Li, Zixuan Cao, Erwan Yang, Mingdong Bao, Haofuzi Zhang, Zhuoyuan Zhang, Dan Liu, Min Zhang, Xiangyu Gao, Junmiao Ge, Xiaofan Jiang, Zhicheng Tian, Peng Luo · 发表于：Cell Death Discovery · 年份：2025 · DOI：10.1038/s41420-025-02337-8 · 被引用次数：13 · 研究领域：Mitochondrial Function and Pathology、Cancer, Hypoxia, and Metabolism、High Altitude and Hypoxia

Traumatic brain injury (TBI) is one of the leading causes of disability and mortality, which was classified as low-altitude TBI and high-altitude TBI. A large amount of literature shows that high-altitude TBI is associated with more severe neurological impairments and higher mortality rates compared to low-altitude TBI, due to the special environment of high-altitude hypoxia. However, the role of high-altitude hypoxia in the pathogenesis of TBI remains unclear. In order to deeply investigate this scientific issue, we constructed a high-altitude hypoxic TBI model at different altitudes and used animal behavioral assessments (Modified neurological severity score, rotarod test, elevated plus maze test) as well as histopathological analyses (brain gross specimens, brain water content, Evans blue content, hypoxia inducible factor-1α, Hematoxylin-Eosin staining and ROS detection) to reveal its underlying principles and characteristics. We found that with higher altitude, TBI-induced neurological deficits were more severe and the associated histopathological changes were more significant. Single-nuclear RNA sequencing was subsequently employed to further reveal differential gene expression profiles in high-altitude TBI. We found a significant increase in ferroptosis of astrocytes in cases of high-altitude TBI compared to those at low-altitude TBI. Analyzing transcription factors in depth, we found that Bach1 plays a crucial role in regulating key molecules that induce ferroptosis in...