HADHA-mediated regulation of JAK/STAT3 signaling in glioblastoma: a metabolic-epigenetic axis
Astract Glioblastoma multiforme (GBM) is one of the most aggressive forms of brain cancer, characterized by rapid growth and resistance to conventional therapies. This study investigates the role of HADHA, a key enzyme in fatty acid β-oxidation, in the progression of GBM. we show that the overexpres...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-08-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02660-0 |
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| author | Kan Wang Yifei Xiao Jinxin Wan Yuanqi Chu Ruipeng Zheng Fengjun Lv Guang Yang Mingchun Yang Haitao Ge Yuwen Song Yu Cheng |
| author_facet | Kan Wang Yifei Xiao Jinxin Wan Yuanqi Chu Ruipeng Zheng Fengjun Lv Guang Yang Mingchun Yang Haitao Ge Yuwen Song Yu Cheng |
| author_sort | Kan Wang |
| collection | DOAJ |
| description | Astract Glioblastoma multiforme (GBM) is one of the most aggressive forms of brain cancer, characterized by rapid growth and resistance to conventional therapies. This study investigates the role of HADHA, a key enzyme in fatty acid β-oxidation, in the progression of GBM. we show that the overexpression of HADHA in GBM correlates with a poor prognosis in patients and plays a role in promoting tumor growth and invasion. Mechanistically, HADHA regulates the JAK/STAT3 signaling pathway through modulation of H3K27ac histone acetylation. Knockdown of HADHA results in decreased acetyl-CoA levels, leading to reduced H3K27ac modification and subsequent inhibition of JAK/STAT3 activation. Furthermore, we show that the small molecule JIB-04, which targets HADHA, inhibits GBM cell proliferation and invasion both in vitro and in vivo. Our findings highlight the importance of targeting metabolic enzymes in cancer therapy and suggest that HADHA could represent a potential new therapeutic target for GBM. By targeting the metabolic-epigenetic pathway, this strategy presents a promising approach for treating this devastating disorder. |
| format | Article |
| id | doaj-art-97a218776c744c44a08dbeedf30f3ed4 |
| institution | DOAJ |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-97a218776c744c44a08dbeedf30f3ed42025-08-20T03:04:17ZengNature Publishing GroupCell Death Discovery2058-77162025-08-0111111210.1038/s41420-025-02660-0HADHA-mediated regulation of JAK/STAT3 signaling in glioblastoma: a metabolic-epigenetic axisKan Wang0Yifei Xiao1Jinxin Wan2Yuanqi Chu3Ruipeng Zheng4Fengjun Lv5Guang Yang6Mingchun Yang7Haitao Ge8Yuwen Song9Yu Cheng10Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Neurosurgery, Guangdong Provincial People’s Hospital, Zhuhai Hospital (Jinwan Central Hospital of Zhuhai)Department of Pathology, XD Group hospitalDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Neurosurgery, The Second Affiliated Hospital of Fujian Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of neurosurgery, The Fourth Affiliated Hospital of Harbin Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityAstract Glioblastoma multiforme (GBM) is one of the most aggressive forms of brain cancer, characterized by rapid growth and resistance to conventional therapies. This study investigates the role of HADHA, a key enzyme in fatty acid β-oxidation, in the progression of GBM. we show that the overexpression of HADHA in GBM correlates with a poor prognosis in patients and plays a role in promoting tumor growth and invasion. Mechanistically, HADHA regulates the JAK/STAT3 signaling pathway through modulation of H3K27ac histone acetylation. Knockdown of HADHA results in decreased acetyl-CoA levels, leading to reduced H3K27ac modification and subsequent inhibition of JAK/STAT3 activation. Furthermore, we show that the small molecule JIB-04, which targets HADHA, inhibits GBM cell proliferation and invasion both in vitro and in vivo. Our findings highlight the importance of targeting metabolic enzymes in cancer therapy and suggest that HADHA could represent a potential new therapeutic target for GBM. By targeting the metabolic-epigenetic pathway, this strategy presents a promising approach for treating this devastating disorder.https://doi.org/10.1038/s41420-025-02660-0 |
| spellingShingle | Kan Wang Yifei Xiao Jinxin Wan Yuanqi Chu Ruipeng Zheng Fengjun Lv Guang Yang Mingchun Yang Haitao Ge Yuwen Song Yu Cheng HADHA-mediated regulation of JAK/STAT3 signaling in glioblastoma: a metabolic-epigenetic axis Cell Death Discovery |
| title | HADHA-mediated regulation of JAK/STAT3 signaling in glioblastoma: a metabolic-epigenetic axis |
| title_full | HADHA-mediated regulation of JAK/STAT3 signaling in glioblastoma: a metabolic-epigenetic axis |
| title_fullStr | HADHA-mediated regulation of JAK/STAT3 signaling in glioblastoma: a metabolic-epigenetic axis |
| title_full_unstemmed | HADHA-mediated regulation of JAK/STAT3 signaling in glioblastoma: a metabolic-epigenetic axis |
| title_short | HADHA-mediated regulation of JAK/STAT3 signaling in glioblastoma: a metabolic-epigenetic axis |
| title_sort | hadha mediated regulation of jak stat3 signaling in glioblastoma a metabolic epigenetic axis |
| url | https://doi.org/10.1038/s41420-025-02660-0 |
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