The critical role of MLKL in hemorrhagic stroke and the therapeutic potential of its associated protein network
IntroductionMixed Lineage Kinase Domain-Like Protein (MLKL), as the executor of necroptosis and a critical factor in the inflammation, has been shown to be associated with the progression of hemorrhagic stroke. Studies identified MLKL is a promoting factor in this process, suggesting its potential a...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2024.1509877/full |
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| author | Yi Wang Yi Wang Moran Xu Xiaoli Zuo Sheng Wang Yong Yu Zhaobing Gao Zhaobing Gao Jingbo Qie Ye Jiang Fang Huang Bingqing Xia Bingqing Xia |
| author_facet | Yi Wang Yi Wang Moran Xu Xiaoli Zuo Sheng Wang Yong Yu Zhaobing Gao Zhaobing Gao Jingbo Qie Ye Jiang Fang Huang Bingqing Xia Bingqing Xia |
| author_sort | Yi Wang |
| collection | DOAJ |
| description | IntroductionMixed Lineage Kinase Domain-Like Protein (MLKL), as the executor of necroptosis and a critical factor in the inflammation, has been shown to be associated with the progression of hemorrhagic stroke. Studies identified MLKL is a promoting factor in this process, suggesting its potential as a therapeutic target to mitigate posthemorrhagic stroke damage. However, the mechanisms by which MLKL functions in the process of intracerebral hemorrhage (ICH)-induced damage remain unclear.MethodsHere, we explored the correlation between MLKL and pathological damage in ICH patients through histopathological staining and RT-qPCR. Furthermore, we established an intracerebral hemorrhage model by collagenase IV injection in WT and Mlkl-/- mice. Subsequently, we investigated the impact of MLKL knockout on ICH pathological damage through behavioral tests, Western blotting, and RT-qPCR. Finally, we performed a proteomic analysis via LC-MS/MS to explore the potential interacting proteins of MLKL in the progression of ICH.ResultsWe found that MLKL is highly expressed in the brain tissue of ICH patients and is positively correlated with the extent of injury. However, we found that Mlkl knockout alone was insufficient to fully reverse neuroinflammation and pathological damage. Although Mlkl knockout has a limited effect on alleviating ICH damage, proteomics results indicate that MLKL can mitigate changes in proteins associated with inflammation, metabolism, and coagulation pathways, suggesting that MLKL may exert its effects through these pathways.DiscussionIn summary, our results suggest that although MLKL is associated with the progression of ICH, single knockout of Mlkl is insufficient to fully reverse the pathological damage of ICH. Proteomic analysis indicates that co-targeting MLKL and its associated protein network may yield better therapeutic outcomes for hemorrhagic stroke. |
| format | Article |
| id | doaj-art-158ef4eedb1242ca802b710e7a455cf3 |
| institution | Kabale University |
| issn | 2296-634X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj-art-158ef4eedb1242ca802b710e7a455cf32025-01-20T07:20:26ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2025-01-011210.3389/fcell.2024.15098771509877The critical role of MLKL in hemorrhagic stroke and the therapeutic potential of its associated protein networkYi Wang0Yi Wang1Moran Xu2Xiaoli Zuo3Sheng Wang4Yong Yu5Zhaobing Gao6Zhaobing Gao7Jingbo Qie8Ye Jiang9Fang Huang10Bingqing Xia11Bingqing Xia12Department of Translational Neuroscience, Jing’an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, ChinaStake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaDepartment of Digestive Diseases, Huashan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, ChinaStake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaDepartment of Digestive Diseases, Huashan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, ChinaDepartment of Neurosurgery Zhongshan Hospital Fudan University, National Medical Center, Shanghai, ChinaStake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaShanghai Fifth People's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, ChinaDepartment of Neurosurgery, Minhang Hospital, Fudan University, Shanghai, ChinaDepartment of Translational Neuroscience, Jing’an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, ChinaStake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaIntroductionMixed Lineage Kinase Domain-Like Protein (MLKL), as the executor of necroptosis and a critical factor in the inflammation, has been shown to be associated with the progression of hemorrhagic stroke. Studies identified MLKL is a promoting factor in this process, suggesting its potential as a therapeutic target to mitigate posthemorrhagic stroke damage. However, the mechanisms by which MLKL functions in the process of intracerebral hemorrhage (ICH)-induced damage remain unclear.MethodsHere, we explored the correlation between MLKL and pathological damage in ICH patients through histopathological staining and RT-qPCR. Furthermore, we established an intracerebral hemorrhage model by collagenase IV injection in WT and Mlkl-/- mice. Subsequently, we investigated the impact of MLKL knockout on ICH pathological damage through behavioral tests, Western blotting, and RT-qPCR. Finally, we performed a proteomic analysis via LC-MS/MS to explore the potential interacting proteins of MLKL in the progression of ICH.ResultsWe found that MLKL is highly expressed in the brain tissue of ICH patients and is positively correlated with the extent of injury. However, we found that Mlkl knockout alone was insufficient to fully reverse neuroinflammation and pathological damage. Although Mlkl knockout has a limited effect on alleviating ICH damage, proteomics results indicate that MLKL can mitigate changes in proteins associated with inflammation, metabolism, and coagulation pathways, suggesting that MLKL may exert its effects through these pathways.DiscussionIn summary, our results suggest that although MLKL is associated with the progression of ICH, single knockout of Mlkl is insufficient to fully reverse the pathological damage of ICH. Proteomic analysis indicates that co-targeting MLKL and its associated protein network may yield better therapeutic outcomes for hemorrhagic stroke.https://www.frontiersin.org/articles/10.3389/fcell.2024.1509877/fullmlklICHhemorrhagic strokeneuroinflammationLC-MS/MS |
| spellingShingle | Yi Wang Yi Wang Moran Xu Xiaoli Zuo Sheng Wang Yong Yu Zhaobing Gao Zhaobing Gao Jingbo Qie Ye Jiang Fang Huang Bingqing Xia Bingqing Xia The critical role of MLKL in hemorrhagic stroke and the therapeutic potential of its associated protein network Frontiers in Cell and Developmental Biology mlkl ICH hemorrhagic stroke neuroinflammation LC-MS/MS |
| title | The critical role of MLKL in hemorrhagic stroke and the therapeutic potential of its associated protein network |
| title_full | The critical role of MLKL in hemorrhagic stroke and the therapeutic potential of its associated protein network |
| title_fullStr | The critical role of MLKL in hemorrhagic stroke and the therapeutic potential of its associated protein network |
| title_full_unstemmed | The critical role of MLKL in hemorrhagic stroke and the therapeutic potential of its associated protein network |
| title_short | The critical role of MLKL in hemorrhagic stroke and the therapeutic potential of its associated protein network |
| title_sort | critical role of mlkl in hemorrhagic stroke and the therapeutic potential of its associated protein network |
| topic | mlkl ICH hemorrhagic stroke neuroinflammation LC-MS/MS |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2024.1509877/full |
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