High-altitude hypoxia aggravated neurological deficits in mice induced by traumatic brain injury via BACH1 mediating astrocytic ferroptosis
Abstract 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...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02337-8 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Peng Zou |
| collection | DOAJ |
| description | Abstract 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 astrocytes following high-altitude TBI. Down-regulation of Bach1 can effectively alleviate high-altitude TBI-induced neurological deficits and histopathological changes in mice. In conclusion, high-altitude hypoxia may significantly enhance the ferroptosis of astrocytes and aggravate TBI by up-regulating Bach1 expression. Our study provides a theoretical foundation for further understanding of the mechanism of high-altitude hypoxic TBI and targeted intervention therapy. |
| format | Article |
| id | doaj-art-db4e97d941624fd0a8c1e5f70da171e6 |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-db4e97d941624fd0a8c1e5f70da171e62025-02-09T12:12:33ZengNature Publishing GroupCell Death Discovery2058-77162025-02-0111111610.1038/s41420-025-02337-8High-altitude hypoxia aggravated neurological deficits in mice induced by traumatic brain injury via BACH1 mediating astrocytic ferroptosisPeng Zou0Tianjing Li1Zixuan Cao2Erwan Yang3Mingdong Bao4Haofuzi Zhang5Zhuoyuan Zhang6Dan Liu7Min Zhang8Xiangyu Gao9Junmiao Ge10Xiaofan Jiang11Zhicheng Tian12Peng Luo13Department of Neurosurgery, Xijing Hospital, Fourth Military Medical UniversityDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical UniversityDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical UniversityDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical UniversityDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical UniversityDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical UniversityDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical UniversityDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical UniversityDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical UniversityDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical UniversityDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical UniversityDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical UniversityDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical UniversityDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical UniversityAbstract 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 astrocytes following high-altitude TBI. Down-regulation of Bach1 can effectively alleviate high-altitude TBI-induced neurological deficits and histopathological changes in mice. In conclusion, high-altitude hypoxia may significantly enhance the ferroptosis of astrocytes and aggravate TBI by up-regulating Bach1 expression. Our study provides a theoretical foundation for further understanding of the mechanism of high-altitude hypoxic TBI and targeted intervention therapy.https://doi.org/10.1038/s41420-025-02337-8 |
| spellingShingle | 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 High-altitude hypoxia aggravated neurological deficits in mice induced by traumatic brain injury via BACH1 mediating astrocytic ferroptosis Cell Death Discovery |
| title | High-altitude hypoxia aggravated neurological deficits in mice induced by traumatic brain injury via BACH1 mediating astrocytic ferroptosis |
| title_full | High-altitude hypoxia aggravated neurological deficits in mice induced by traumatic brain injury via BACH1 mediating astrocytic ferroptosis |
| title_fullStr | High-altitude hypoxia aggravated neurological deficits in mice induced by traumatic brain injury via BACH1 mediating astrocytic ferroptosis |
| title_full_unstemmed | High-altitude hypoxia aggravated neurological deficits in mice induced by traumatic brain injury via BACH1 mediating astrocytic ferroptosis |
| title_short | High-altitude hypoxia aggravated neurological deficits in mice induced by traumatic brain injury via BACH1 mediating astrocytic ferroptosis |
| title_sort | high altitude hypoxia aggravated neurological deficits in mice induced by traumatic brain injury via bach1 mediating astrocytic ferroptosis |
| url | https://doi.org/10.1038/s41420-025-02337-8 |
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