SIRT1 Alleviates Mitochondrial Fission and Necroptosis in Cerebral Ischemia/Reperfusion Injury via SIRT1–RIP1 Signaling Pathway
ABSTRACT Programmed cell death, including necroptosis, plays a critical role in the pathogenesis of cerebral ischemia/reperfusion injury (CIRI). Silent information regulator 1 (SIRT1) has been identified as a potential therapeutic target for CIRI, yet its precise role in regulating necroptosis remai...
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Wiley
2025-03-01
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| Online Access: | https://doi.org/10.1002/mco2.70118 |
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| author | Xuan Wei Hanjing Guo Guangshan Huang Haoyue Luo Lipeng Gong Pan Meng Jiyong Liu Wenli Zhang Zhigang Mei |
| author_facet | Xuan Wei Hanjing Guo Guangshan Huang Haoyue Luo Lipeng Gong Pan Meng Jiyong Liu Wenli Zhang Zhigang Mei |
| author_sort | Xuan Wei |
| collection | DOAJ |
| description | ABSTRACT Programmed cell death, including necroptosis, plays a critical role in the pathogenesis of cerebral ischemia/reperfusion injury (CIRI). Silent information regulator 1 (SIRT1) has been identified as a potential therapeutic target for CIRI, yet its precise role in regulating necroptosis remains controversial. Furthermore, the potential interaction between SIRT1 and receptor‐interacting protein kinase 1 (RIP1) in this context is not fully understood. Sanpian Decoction (SPD), a classical traditional herbal formula, was previously shown to enhance SIRT1 expression in our studies. Our findings demonstrated that, both in vivo and in vitro, CIRI was associated with a decrease in SIRT1 levels and phosphorylated dynamin‐related protein 1 (p‐DRP1) at Ser637, alongside an increase in RIP1 and other necroptosis‐related proteins. Co‐immunoprecipitation and immunofluorescence analyses revealed a weakened interaction between SIRT1 and RIP1. Furthermore, abnormal mitochondrial fission and dysfunction were mediated through the phosphoglycerate mutase 5–DRP1 pathway. Notably, SPD treatment improved neurological outcomes and reversed these pathological changes by enhancing the SIRT1–RIP1 interaction. In conclusion, this study suggests that SIRT1 is a promising therapeutic target for CIRI, capable of inhibiting necroptosis and mitigating mitochondrial fission via the SIRT1–RIP1 pathway. SPD exhibits therapeutic potential by activating SIRT1, thereby attenuating necroptosis and mitochondrial fission during CIRI. |
| format | Article |
| id | doaj-art-65ed10f39af04a61b5a0279bd024f97c |
| institution | Kabale University |
| issn | 2688-2663 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
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| series | MedComm |
| spelling | doaj-art-65ed10f39af04a61b5a0279bd024f97c2025-08-20T03:40:28ZengWileyMedComm2688-26632025-03-0163n/an/a10.1002/mco2.70118SIRT1 Alleviates Mitochondrial Fission and Necroptosis in Cerebral Ischemia/Reperfusion Injury via SIRT1–RIP1 Signaling PathwayXuan Wei0Hanjing Guo1Guangshan Huang2Haoyue Luo3Lipeng Gong4Pan Meng5Jiyong Liu6Wenli Zhang7Zhigang Mei8Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio‐Cerebral Diseases College of Integrated Traditional Chinese and Western Medicine Hunan University of Chinese Medicine Changsha Hunan ChinaKey Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio‐Cerebral Diseases College of Integrated Traditional Chinese and Western Medicine Hunan University of Chinese Medicine Changsha Hunan ChinaKey Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio‐Cerebral Diseases College of Integrated Traditional Chinese and Western Medicine Hunan University of Chinese Medicine Changsha Hunan ChinaKey Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio‐Cerebral Diseases College of Integrated Traditional Chinese and Western Medicine Hunan University of Chinese Medicine Changsha Hunan ChinaKey Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio‐Cerebral Diseases College of Integrated Traditional Chinese and Western Medicine Hunan University of Chinese Medicine Changsha Hunan ChinaKey Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio‐Cerebral Diseases College of Integrated Traditional Chinese and Western Medicine Hunan University of Chinese Medicine Changsha Hunan ChinaHunan Provincial Key Laboratory of Traditional Chinese Medicine Diagnostics Hunan University of Chinese Medicine Changsha Hunan ChinaSchool of Pharmacy Hunan University of Chinese Medicine Changsha Hunan ChinaKey Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio‐Cerebral Diseases College of Integrated Traditional Chinese and Western Medicine Hunan University of Chinese Medicine Changsha Hunan ChinaABSTRACT Programmed cell death, including necroptosis, plays a critical role in the pathogenesis of cerebral ischemia/reperfusion injury (CIRI). Silent information regulator 1 (SIRT1) has been identified as a potential therapeutic target for CIRI, yet its precise role in regulating necroptosis remains controversial. Furthermore, the potential interaction between SIRT1 and receptor‐interacting protein kinase 1 (RIP1) in this context is not fully understood. Sanpian Decoction (SPD), a classical traditional herbal formula, was previously shown to enhance SIRT1 expression in our studies. Our findings demonstrated that, both in vivo and in vitro, CIRI was associated with a decrease in SIRT1 levels and phosphorylated dynamin‐related protein 1 (p‐DRP1) at Ser637, alongside an increase in RIP1 and other necroptosis‐related proteins. Co‐immunoprecipitation and immunofluorescence analyses revealed a weakened interaction between SIRT1 and RIP1. Furthermore, abnormal mitochondrial fission and dysfunction were mediated through the phosphoglycerate mutase 5–DRP1 pathway. Notably, SPD treatment improved neurological outcomes and reversed these pathological changes by enhancing the SIRT1–RIP1 interaction. In conclusion, this study suggests that SIRT1 is a promising therapeutic target for CIRI, capable of inhibiting necroptosis and mitigating mitochondrial fission via the SIRT1–RIP1 pathway. SPD exhibits therapeutic potential by activating SIRT1, thereby attenuating necroptosis and mitochondrial fission during CIRI.https://doi.org/10.1002/mco2.70118cerebral ischemia/reperfusion injuryDRP1mitochondrial fissionnecroptosisRIP1SIRT1 |
| spellingShingle | Xuan Wei Hanjing Guo Guangshan Huang Haoyue Luo Lipeng Gong Pan Meng Jiyong Liu Wenli Zhang Zhigang Mei SIRT1 Alleviates Mitochondrial Fission and Necroptosis in Cerebral Ischemia/Reperfusion Injury via SIRT1–RIP1 Signaling Pathway MedComm cerebral ischemia/reperfusion injury DRP1 mitochondrial fission necroptosis RIP1 SIRT1 |
| title | SIRT1 Alleviates Mitochondrial Fission and Necroptosis in Cerebral Ischemia/Reperfusion Injury via SIRT1–RIP1 Signaling Pathway |
| title_full | SIRT1 Alleviates Mitochondrial Fission and Necroptosis in Cerebral Ischemia/Reperfusion Injury via SIRT1–RIP1 Signaling Pathway |
| title_fullStr | SIRT1 Alleviates Mitochondrial Fission and Necroptosis in Cerebral Ischemia/Reperfusion Injury via SIRT1–RIP1 Signaling Pathway |
| title_full_unstemmed | SIRT1 Alleviates Mitochondrial Fission and Necroptosis in Cerebral Ischemia/Reperfusion Injury via SIRT1–RIP1 Signaling Pathway |
| title_short | SIRT1 Alleviates Mitochondrial Fission and Necroptosis in Cerebral Ischemia/Reperfusion Injury via SIRT1–RIP1 Signaling Pathway |
| title_sort | sirt1 alleviates mitochondrial fission and necroptosis in cerebral ischemia reperfusion injury via sirt1 rip1 signaling pathway |
| topic | cerebral ischemia/reperfusion injury DRP1 mitochondrial fission necroptosis RIP1 SIRT1 |
| url | https://doi.org/10.1002/mco2.70118 |
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