Inhibition of OGFOD1 by FG4592 confers neuroprotection by activating unfolded protein response and autophagy after ischemic stroke
Abstract Background Acute ischemic stroke is a common neurological disease with a significant financial burden but lacks effective drugs. Hypoxia-inducible factor (HIF) and prolyl hydroxylases (PHDs) participate in the pathophysiological process of ischemia. However, whether FG4592, the first clinic...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-024-04993-3 |
| _version_ | 1797266653802659840 |
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| author | Jian Xie Yuan Zhang Bin Li Wen Xi Yu Wang Lu Li Chenchen Liu Ling Shen Bing Han Yan Kong HongHong Yao Zhijun Zhang |
| author_facet | Jian Xie Yuan Zhang Bin Li Wen Xi Yu Wang Lu Li Chenchen Liu Ling Shen Bing Han Yan Kong HongHong Yao Zhijun Zhang |
| author_sort | Jian Xie |
| collection | DOAJ |
| description | Abstract Background Acute ischemic stroke is a common neurological disease with a significant financial burden but lacks effective drugs. Hypoxia-inducible factor (HIF) and prolyl hydroxylases (PHDs) participate in the pathophysiological process of ischemia. However, whether FG4592, the first clinically approved PHDs inhibitor, can alleviate ischemic brain injury remains unclear. Methods The infarct volumes and behaviour tests were first analyzed in mice after ischemic stroke with systemic administration of FG4592. The knockdown of HIF-1α and pretreatments of HIF-1/2α inhibitors were then used to verify whether the neuroprotection of FG4592 is HIF-dependent. The targets predicting and molecular docking methods were applied to find other targets of FG4592. Molecular, cell biological and gene knockdown methods were finally conducted to explore the potential neuroprotective mechanisms of FG4592. Results We found that the systemic administration of FG4592 decreased infarct volume and improved neurological defects of mice after transient or permanent ischemia. Meanwhile, FG4592 also activated autophagy and inhibited apoptosis in peri-infarct tissue of mice brains. However, in vitro and in vivo results suggested that the neuroprotection of FG4592 was not classical HIF-dependent. 2-oxoglutarate and iron-dependent oxygenase domain-containing protein 1 (OGFOD1) was found to be a novel target of FG4592 and regulated the Pro-62 hydroxylation in the small ribosomal protein s23 (Rps23) with the help of target predicting and molecular docking methods. Subsequently, the knockdown of OGFOD1 protected the cell against ischemia/reperfusion injury and activated unfolded protein response (UPR) and autophagy. Moreover, FG4592 was also found to activate UPR and autophagic flux in HIF-1α independent manner. Blocking UPR attenuated the neuroprotection, pro-autophagy effect and anti-apoptosis ability of FG4592. Conclusion This study demonstrated that FG4592 could be a candidate drug for treating ischemic stroke. The neuroprotection of FG4592 might be mediated by inhibiting alternative target OGFOD1, which activated the UPR and autophagy and inhibited apoptosis after ischemic injury. The inhibition of OGFOD1 is a novel therapy for ischemic stroke. |
| first_indexed | 2024-04-25T01:04:07Z |
| format | Article |
| id | doaj.art-ae9a0df411544553a04a52b969b7b113 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-25T01:04:07Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-ae9a0df411544553a04a52b969b7b1132024-03-10T12:21:05ZengBMCJournal of Translational Medicine1479-58762024-03-0122112710.1186/s12967-024-04993-3Inhibition of OGFOD1 by FG4592 confers neuroprotection by activating unfolded protein response and autophagy after ischemic strokeJian Xie0Yuan Zhang1Bin Li2Wen Xi3Yu Wang4Lu Li5Chenchen Liu6Ling Shen7Bing Han8Yan Kong9HongHong Yao10Zhijun Zhang11Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Institution of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease, Southeast UniversityDepartment of Pharmacology, School of Medicine, Southeast UniversityDepartment of Pharmacology, School of Medicine, Southeast UniversityDepartment of Pharmacology, School of Medicine, Southeast UniversityDepartment of Pharmacology, School of Medicine, Southeast UniversityDepartment of Pharmacology, School of Medicine, Southeast UniversityDepartment of Pharmacology, School of Medicine, Southeast UniversityDepartment of Pharmacology, School of Medicine, Southeast UniversityDepartment of Pharmacology, School of Medicine, Southeast UniversityDepartment of Biochemistry and Molecular Biology, School of Medicine, Southeast UniversityDepartment of Pharmacology, School of Medicine, Southeast UniversityDepartment of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Institution of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease, Southeast UniversityAbstract Background Acute ischemic stroke is a common neurological disease with a significant financial burden but lacks effective drugs. Hypoxia-inducible factor (HIF) and prolyl hydroxylases (PHDs) participate in the pathophysiological process of ischemia. However, whether FG4592, the first clinically approved PHDs inhibitor, can alleviate ischemic brain injury remains unclear. Methods The infarct volumes and behaviour tests were first analyzed in mice after ischemic stroke with systemic administration of FG4592. The knockdown of HIF-1α and pretreatments of HIF-1/2α inhibitors were then used to verify whether the neuroprotection of FG4592 is HIF-dependent. The targets predicting and molecular docking methods were applied to find other targets of FG4592. Molecular, cell biological and gene knockdown methods were finally conducted to explore the potential neuroprotective mechanisms of FG4592. Results We found that the systemic administration of FG4592 decreased infarct volume and improved neurological defects of mice after transient or permanent ischemia. Meanwhile, FG4592 also activated autophagy and inhibited apoptosis in peri-infarct tissue of mice brains. However, in vitro and in vivo results suggested that the neuroprotection of FG4592 was not classical HIF-dependent. 2-oxoglutarate and iron-dependent oxygenase domain-containing protein 1 (OGFOD1) was found to be a novel target of FG4592 and regulated the Pro-62 hydroxylation in the small ribosomal protein s23 (Rps23) with the help of target predicting and molecular docking methods. Subsequently, the knockdown of OGFOD1 protected the cell against ischemia/reperfusion injury and activated unfolded protein response (UPR) and autophagy. Moreover, FG4592 was also found to activate UPR and autophagic flux in HIF-1α independent manner. Blocking UPR attenuated the neuroprotection, pro-autophagy effect and anti-apoptosis ability of FG4592. Conclusion This study demonstrated that FG4592 could be a candidate drug for treating ischemic stroke. The neuroprotection of FG4592 might be mediated by inhibiting alternative target OGFOD1, which activated the UPR and autophagy and inhibited apoptosis after ischemic injury. The inhibition of OGFOD1 is a novel therapy for ischemic stroke.https://doi.org/10.1186/s12967-024-04993-3FG4592Ischemic strokeOGFOD1Unfolded protein responseAutophagy |
| spellingShingle | Jian Xie Yuan Zhang Bin Li Wen Xi Yu Wang Lu Li Chenchen Liu Ling Shen Bing Han Yan Kong HongHong Yao Zhijun Zhang Inhibition of OGFOD1 by FG4592 confers neuroprotection by activating unfolded protein response and autophagy after ischemic stroke Journal of Translational Medicine FG4592 Ischemic stroke OGFOD1 Unfolded protein response Autophagy |
| title | Inhibition of OGFOD1 by FG4592 confers neuroprotection by activating unfolded protein response and autophagy after ischemic stroke |
| title_full | Inhibition of OGFOD1 by FG4592 confers neuroprotection by activating unfolded protein response and autophagy after ischemic stroke |
| title_fullStr | Inhibition of OGFOD1 by FG4592 confers neuroprotection by activating unfolded protein response and autophagy after ischemic stroke |
| title_full_unstemmed | Inhibition of OGFOD1 by FG4592 confers neuroprotection by activating unfolded protein response and autophagy after ischemic stroke |
| title_short | Inhibition of OGFOD1 by FG4592 confers neuroprotection by activating unfolded protein response and autophagy after ischemic stroke |
| title_sort | inhibition of ogfod1 by fg4592 confers neuroprotection by activating unfolded protein response and autophagy after ischemic stroke |
| topic | FG4592 Ischemic stroke OGFOD1 Unfolded protein response Autophagy |
| url | https://doi.org/10.1186/s12967-024-04993-3 |
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