DDX3X promotes endoplasmic reticulum protein reprogramming via interaction with ERN1 to amplify cerebral ischemia/reperfusion injury
Abstract Background Reperfusion therapy is a critical intervention to salvage acute cerebral ischemia. However, reperfusion itself induces cerebral ischemia/reperfusion (I/R) injury. Recent evidence suggests that DEAD-box helicase 3, X-linked (DDX3X) and Endoplasmic Reticulum to Nucleus Signaling 1...
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BMC
2025-07-01
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| Series: | European Journal of Medical Research |
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| Online Access: | https://doi.org/10.1186/s40001-025-02813-y |
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| author | QiaoHui Du YuQian Liu JingLong Guo |
| author_facet | QiaoHui Du YuQian Liu JingLong Guo |
| author_sort | QiaoHui Du |
| collection | DOAJ |
| description | Abstract Background Reperfusion therapy is a critical intervention to salvage acute cerebral ischemia. However, reperfusion itself induces cerebral ischemia/reperfusion (I/R) injury. Recent evidence suggests that DEAD-box helicase 3, X-linked (DDX3X) and Endoplasmic Reticulum to Nucleus Signaling 1 (ERN1) play pivotal roles in various diseases, particularly those affecting the nervous system. However, the exact roles of DDX3X and ERN1 in cerebral I/R injury remain unclear. Methods We used Sprague–Dawley (SD) rats subjected to middle cerebral artery occlusion (MCAO) surgery and PC12 cells exposed to oxygen–glucose deprivation/reoxygenation (OGD/R) to establish cerebral I/R injury models. Western blotting, immunohistochemistry, and co-immunoprecipitation were employed to assess the expression and interaction of DDX3X and ERN1. CCK-8 assay and flow cytometry were used to evaluate cell viability and apoptosis. Western blotting was performed to measure key endoplasmic reticulum stress (ERS) markers and downstream targets. Pro-inflammatory cytokines were quantified by ELISA. Results DDX3X and ERN1 were significantly upregulated in both OGD/R-treated PC12 cells and MCAO rat brain tissue. Importantly, DDX3X was shown to positively regulate ERN1 expression, leading to increased apoptosis, ERS, oxidative stress, and inflammation in both cellular and animal models. These processes collectively exacerbated cerebral injury, reinforcing the pathological role of DDX3X and ERN1 interaction in the progression of cerebral I/R injury. Conclusion DDX3X enhances cerebral I/R injury by interacting with ERN1, which triggers the reprogramming of endoplasmic reticulum protein responses, amplifying ERS, apoptosis, and inflammation. |
| format | Article |
| id | doaj-art-2b2d962ace254400a4552c3a2527c8ea |
| institution | Kabale University |
| issn | 2047-783X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | European Journal of Medical Research |
| spelling | doaj-art-2b2d962ace254400a4552c3a2527c8ea2025-08-20T03:45:24ZengBMCEuropean Journal of Medical Research2047-783X2025-07-0130111310.1186/s40001-025-02813-yDDX3X promotes endoplasmic reticulum protein reprogramming via interaction with ERN1 to amplify cerebral ischemia/reperfusion injuryQiaoHui Du0YuQian Liu1JingLong Guo2Health Management Center, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical UniversityHealth Management Center, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical UniversityDepartment of Hepatobiliary Surgery, Shandong Provincial Third Hospital, Shandong UniversityAbstract Background Reperfusion therapy is a critical intervention to salvage acute cerebral ischemia. However, reperfusion itself induces cerebral ischemia/reperfusion (I/R) injury. Recent evidence suggests that DEAD-box helicase 3, X-linked (DDX3X) and Endoplasmic Reticulum to Nucleus Signaling 1 (ERN1) play pivotal roles in various diseases, particularly those affecting the nervous system. However, the exact roles of DDX3X and ERN1 in cerebral I/R injury remain unclear. Methods We used Sprague–Dawley (SD) rats subjected to middle cerebral artery occlusion (MCAO) surgery and PC12 cells exposed to oxygen–glucose deprivation/reoxygenation (OGD/R) to establish cerebral I/R injury models. Western blotting, immunohistochemistry, and co-immunoprecipitation were employed to assess the expression and interaction of DDX3X and ERN1. CCK-8 assay and flow cytometry were used to evaluate cell viability and apoptosis. Western blotting was performed to measure key endoplasmic reticulum stress (ERS) markers and downstream targets. Pro-inflammatory cytokines were quantified by ELISA. Results DDX3X and ERN1 were significantly upregulated in both OGD/R-treated PC12 cells and MCAO rat brain tissue. Importantly, DDX3X was shown to positively regulate ERN1 expression, leading to increased apoptosis, ERS, oxidative stress, and inflammation in both cellular and animal models. These processes collectively exacerbated cerebral injury, reinforcing the pathological role of DDX3X and ERN1 interaction in the progression of cerebral I/R injury. Conclusion DDX3X enhances cerebral I/R injury by interacting with ERN1, which triggers the reprogramming of endoplasmic reticulum protein responses, amplifying ERS, apoptosis, and inflammation.https://doi.org/10.1186/s40001-025-02813-yProtein interactionEndoplasmic reticulum reprogrammingCerebral ischemia/reperfusion injuryGene silencing |
| spellingShingle | QiaoHui Du YuQian Liu JingLong Guo DDX3X promotes endoplasmic reticulum protein reprogramming via interaction with ERN1 to amplify cerebral ischemia/reperfusion injury European Journal of Medical Research Protein interaction Endoplasmic reticulum reprogramming Cerebral ischemia/reperfusion injury Gene silencing |
| title | DDX3X promotes endoplasmic reticulum protein reprogramming via interaction with ERN1 to amplify cerebral ischemia/reperfusion injury |
| title_full | DDX3X promotes endoplasmic reticulum protein reprogramming via interaction with ERN1 to amplify cerebral ischemia/reperfusion injury |
| title_fullStr | DDX3X promotes endoplasmic reticulum protein reprogramming via interaction with ERN1 to amplify cerebral ischemia/reperfusion injury |
| title_full_unstemmed | DDX3X promotes endoplasmic reticulum protein reprogramming via interaction with ERN1 to amplify cerebral ischemia/reperfusion injury |
| title_short | DDX3X promotes endoplasmic reticulum protein reprogramming via interaction with ERN1 to amplify cerebral ischemia/reperfusion injury |
| title_sort | ddx3x promotes endoplasmic reticulum protein reprogramming via interaction with ern1 to amplify cerebral ischemia reperfusion injury |
| topic | Protein interaction Endoplasmic reticulum reprogramming Cerebral ischemia/reperfusion injury Gene silencing |
| url | https://doi.org/10.1186/s40001-025-02813-y |
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