m6A reader YTHDC2 mediates NCOA4 mRNA stability affecting ferritinophagy to alleviate secondary injury after intracerebral haemorrhage
Oxidative stress and neuronal dysfunction caused by intracerebral haemorrhage (ICH) can lead to secondary injury. The m6A modification has been implicated in the progression of ICH. This study aimed to investigate the role of the m6A reader YTHDC2 in ICH-induced secondary injury. ICH models were est...
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Taylor & Francis Group
2024-12-01
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| Series: | Epigenetics |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/15592294.2024.2326868 |
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| author | Fengfeng Li Fang Wang Lei Wang Jianhua Wang Shanshan Wei Junjun Meng Yanan Li Lei Feng Pei Jiang |
| author_facet | Fengfeng Li Fang Wang Lei Wang Jianhua Wang Shanshan Wei Junjun Meng Yanan Li Lei Feng Pei Jiang |
| author_sort | Fengfeng Li |
| collection | DOAJ |
| description | Oxidative stress and neuronal dysfunction caused by intracerebral haemorrhage (ICH) can lead to secondary injury. The m6A modification has been implicated in the progression of ICH. This study aimed to investigate the role of the m6A reader YTHDC2 in ICH-induced secondary injury. ICH models were established in rats using autologous blood injection, and neuronal cell models were induced with Hemin. Experiments were conducted to overexpress YTH domain containing 2 (YTHDC2) and examine its effects on neuronal dysfunction, brain injury, and neuronal ferritinophagy. RIP-qPCR and METTL3 silencing were performed to investigate the regulation of YTHDC2 on nuclear receptor coactivator 4 (NCOA4). Finally, NCOA4 overexpression was used to validate the regulatory mechanism of YTHDC2 in ICH. The study found that YTHDC2 expression was significantly downregulated in the brain tissues of ICH rats. However, YTHDC2 overexpression improved neuronal dysfunction and reduced brain water content and neuronal death after ICH. Additionally, it reduced levels of ROS, NCOA4, PTGS2, and ATG5 in the brain tissues of ICH rats, while increasing levels of FTH and FTL. YTHDC2 overexpression also decreased levels of MDA and Fe2+ in the serum, while promoting GSH synthesis. In neuronal cells, YTHDC2 overexpression alleviated Hemin-induced injury, which was reversed by Erastin. Mechanistically, YTHDC2-mediated m6A modification destabilized NCOA4 mRNA, thereby reducing ferritinophagy and alleviating secondary injury after ICH. However, the effects of YTHDC2 were counteracted by NCOA4 overexpression. Overall, YTHDC2 plays a protective role in ICH-induced secondary injury by regulating NCOA4-mediated ferritinophagy. |
| format | Article |
| id | doaj-art-8d06a4b1be6442d385607c7a2f52f15c |
| institution | Kabale University |
| issn | 1559-2294 1559-2308 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj-art-8d06a4b1be6442d385607c7a2f52f15c2024-12-09T07:21:35ZengTaylor & Francis GroupEpigenetics1559-22941559-23082024-12-0119110.1080/15592294.2024.2326868m6A reader YTHDC2 mediates NCOA4 mRNA stability affecting ferritinophagy to alleviate secondary injury after intracerebral haemorrhageFengfeng Li0Fang Wang1Lei Wang2Jianhua Wang3Shanshan Wei4Junjun Meng5Yanan Li6Lei Feng7Pei Jiang8Department of Neurosurgery, Tengzhou Central People’s Hospital, Jining Medical University, Tengzhou, ChinaTranslational Pharmaceutical Laboratory, Jining First People’s Hospital, Shandong First Medical University, Jining, ChinaTranslational Pharmaceutical Laboratory, Jining First People’s Hospital, Shandong First Medical University, Jining, ChinaTranslational Pharmaceutical Laboratory, Jining First People’s Hospital, Shandong First Medical University, Jining, ChinaDepartment of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, ChinaTranslational Pharmaceutical Laboratory, Jining First People’s Hospital, Shandong First Medical University, Jining, ChinaTranslational Pharmaceutical Laboratory, Jining First People’s Hospital, Shandong First Medical University, Jining, ChinaDepartment of Neurosurgery, Jining First People’s Hospital, Shandong First Medical University, Jining, ChinaTranslational Pharmaceutical Laboratory, Jining First People’s Hospital, Shandong First Medical University, Jining, ChinaOxidative stress and neuronal dysfunction caused by intracerebral haemorrhage (ICH) can lead to secondary injury. The m6A modification has been implicated in the progression of ICH. This study aimed to investigate the role of the m6A reader YTHDC2 in ICH-induced secondary injury. ICH models were established in rats using autologous blood injection, and neuronal cell models were induced with Hemin. Experiments were conducted to overexpress YTH domain containing 2 (YTHDC2) and examine its effects on neuronal dysfunction, brain injury, and neuronal ferritinophagy. RIP-qPCR and METTL3 silencing were performed to investigate the regulation of YTHDC2 on nuclear receptor coactivator 4 (NCOA4). Finally, NCOA4 overexpression was used to validate the regulatory mechanism of YTHDC2 in ICH. The study found that YTHDC2 expression was significantly downregulated in the brain tissues of ICH rats. However, YTHDC2 overexpression improved neuronal dysfunction and reduced brain water content and neuronal death after ICH. Additionally, it reduced levels of ROS, NCOA4, PTGS2, and ATG5 in the brain tissues of ICH rats, while increasing levels of FTH and FTL. YTHDC2 overexpression also decreased levels of MDA and Fe2+ in the serum, while promoting GSH synthesis. In neuronal cells, YTHDC2 overexpression alleviated Hemin-induced injury, which was reversed by Erastin. Mechanistically, YTHDC2-mediated m6A modification destabilized NCOA4 mRNA, thereby reducing ferritinophagy and alleviating secondary injury after ICH. However, the effects of YTHDC2 were counteracted by NCOA4 overexpression. Overall, YTHDC2 plays a protective role in ICH-induced secondary injury by regulating NCOA4-mediated ferritinophagy.https://www.tandfonline.com/doi/10.1080/15592294.2024.2326868m6AYTHDC2NCOA4ferritinophagyintracerebral haemorrhage |
| spellingShingle | Fengfeng Li Fang Wang Lei Wang Jianhua Wang Shanshan Wei Junjun Meng Yanan Li Lei Feng Pei Jiang m6A reader YTHDC2 mediates NCOA4 mRNA stability affecting ferritinophagy to alleviate secondary injury after intracerebral haemorrhage Epigenetics m6A YTHDC2 NCOA4 ferritinophagy intracerebral haemorrhage |
| title | m6A reader YTHDC2 mediates NCOA4 mRNA stability affecting ferritinophagy to alleviate secondary injury after intracerebral haemorrhage |
| title_full | m6A reader YTHDC2 mediates NCOA4 mRNA stability affecting ferritinophagy to alleviate secondary injury after intracerebral haemorrhage |
| title_fullStr | m6A reader YTHDC2 mediates NCOA4 mRNA stability affecting ferritinophagy to alleviate secondary injury after intracerebral haemorrhage |
| title_full_unstemmed | m6A reader YTHDC2 mediates NCOA4 mRNA stability affecting ferritinophagy to alleviate secondary injury after intracerebral haemorrhage |
| title_short | m6A reader YTHDC2 mediates NCOA4 mRNA stability affecting ferritinophagy to alleviate secondary injury after intracerebral haemorrhage |
| title_sort | m6a reader ythdc2 mediates ncoa4 mrna stability affecting ferritinophagy to alleviate secondary injury after intracerebral haemorrhage |
| topic | m6A YTHDC2 NCOA4 ferritinophagy intracerebral haemorrhage |
| url | https://www.tandfonline.com/doi/10.1080/15592294.2024.2326868 |
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