Gypensapogenin I alleviates PANoptosis, ferroptosis, and oxidative stress in myocardial ischemic–reperfusion injury by targeting the NOX2/AMPK pathway
AimThis study aims to investigate the benefits of gypensapogenin I (GI) on myocardial ischemia–reperfusion injury (MIRI) and the underlying mechanisms.MethodsAn MIRI model was established by ligating the anterior descending coronary artery (LAD) followed by blood flow restoration in mice. Cardiac dy...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2025.1623846/full |
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| author | Yuqiong Chen Bo Guan Jian Lu Xiaopei Yan Chao Huang Yuli Qiu Xinyan Li Xiangyu Sun Lin Chen Wei Li Wenjun Mao Zhongqi Sun Bin Xu Su Li Chao Chen Chao Chen |
| author_facet | Yuqiong Chen Bo Guan Jian Lu Xiaopei Yan Chao Huang Yuli Qiu Xinyan Li Xiangyu Sun Lin Chen Wei Li Wenjun Mao Zhongqi Sun Bin Xu Su Li Chao Chen Chao Chen |
| author_sort | Yuqiong Chen |
| collection | DOAJ |
| description | AimThis study aims to investigate the benefits of gypensapogenin I (GI) on myocardial ischemia–reperfusion injury (MIRI) and the underlying mechanisms.MethodsAn MIRI model was established by ligating the anterior descending coronary artery (LAD) followed by blood flow restoration in mice. Cardiac dysfunction and myocardial infarction size were evaluated by echocardiography and triphenyltetrazolium chloride (TTC) staining. PANoptosis, ferroptosis, and mitochondrial redox state were examined by immunofluorescence, Western blotting, and an ELISA kit. In addition, molecular and biochemical methods were applied to illustrate the exact mechanisms of GI on MIRI.ResultsGI pretreatment alleviated cellular oxidative stress, inhibited PANoptosis and ferroptosis, reduced myocardial infarction area, and improved cardiac function during MIRI. Further results revealed that mitochondrial biogenesis and the anti-oxidative system were impaired in mice suffering from MIRI, and these effects were significantly alleviated by GI treatment via downregulation of the NADPH oxidase 2 (NOX2) level. Moreover, NOX2 promoted mitochondrial dysfunction by suppressing the AMP-activated protein kinase (AMPK)–PGC-1α–Sirt3 signaling pathway. In addition, the NOX2 activator exacerbated oxidative damage and offset all the beneficial effects of GI on mitochondrial function, PANoptosis, and ferroptosis. Meanwhile, reinforced AMPK phosphorylation by GI or AMPK activator (5-aminoimidazole-4-carboxamide ribonucleotide, AICAR) maintained the mitochondrial redox state and biogenesis and suppressed PANoptosis and ferroptosis.ConclusionGI pretreatment protected the cardiomyocytes from MIRI-induced PANoptosis and ferroptosis by maintaining the mitochondrial redox state and biogenesis through the modulation of the NOX2/AMPK signaling pathway. Our findings indicate that GI pretreatment could be a promising therapeutic agent for MIRI treatment. |
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| issn | 2296-634X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| spelling | doaj-art-d27d7ddd5b3a4a27a226833d0e9a1f012025-07-22T05:29:54ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2025-07-011310.3389/fcell.2025.16238461623846Gypensapogenin I alleviates PANoptosis, ferroptosis, and oxidative stress in myocardial ischemic–reperfusion injury by targeting the NOX2/AMPK pathwayYuqiong Chen0Bo Guan1Jian Lu2Xiaopei Yan3Chao Huang4Yuli Qiu5Xinyan Li6Xiangyu Sun7Lin Chen8Wei Li9Wenjun Mao10Zhongqi Sun11Bin Xu12Su Li13Chao Chen14Chao Chen15Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Nanjing, ChinaDepartment of Geriatrics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Nanjing, ChinaDepartment of Emergency and Critical Care Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Nanjing, ChinaDepartment of Respiratory Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Nanjing, ChinaMinistry of Science and Technology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, ChinaDepartment of Nephrology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, ChinaNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaDepartment of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Nanjing, ChinaDepartment of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Nanjing, ChinaDepartment of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Nanjing, ChinaDepartment of Cardiology, Suzhou WuZhong People’s Hospital, Suzhou, Jiangsu, ChinaDepartment of Emergency and Critical Care Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Nanjing, ChinaDepartment of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, ChinaDepartment of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Nanjing, China0Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, ChinaAimThis study aims to investigate the benefits of gypensapogenin I (GI) on myocardial ischemia–reperfusion injury (MIRI) and the underlying mechanisms.MethodsAn MIRI model was established by ligating the anterior descending coronary artery (LAD) followed by blood flow restoration in mice. Cardiac dysfunction and myocardial infarction size were evaluated by echocardiography and triphenyltetrazolium chloride (TTC) staining. PANoptosis, ferroptosis, and mitochondrial redox state were examined by immunofluorescence, Western blotting, and an ELISA kit. In addition, molecular and biochemical methods were applied to illustrate the exact mechanisms of GI on MIRI.ResultsGI pretreatment alleviated cellular oxidative stress, inhibited PANoptosis and ferroptosis, reduced myocardial infarction area, and improved cardiac function during MIRI. Further results revealed that mitochondrial biogenesis and the anti-oxidative system were impaired in mice suffering from MIRI, and these effects were significantly alleviated by GI treatment via downregulation of the NADPH oxidase 2 (NOX2) level. Moreover, NOX2 promoted mitochondrial dysfunction by suppressing the AMP-activated protein kinase (AMPK)–PGC-1α–Sirt3 signaling pathway. In addition, the NOX2 activator exacerbated oxidative damage and offset all the beneficial effects of GI on mitochondrial function, PANoptosis, and ferroptosis. Meanwhile, reinforced AMPK phosphorylation by GI or AMPK activator (5-aminoimidazole-4-carboxamide ribonucleotide, AICAR) maintained the mitochondrial redox state and biogenesis and suppressed PANoptosis and ferroptosis.ConclusionGI pretreatment protected the cardiomyocytes from MIRI-induced PANoptosis and ferroptosis by maintaining the mitochondrial redox state and biogenesis through the modulation of the NOX2/AMPK signaling pathway. Our findings indicate that GI pretreatment could be a promising therapeutic agent for MIRI treatment.https://www.frontiersin.org/articles/10.3389/fcell.2025.1623846/fullgypensapogenin Imyocardial ischemia–reperfusion injuryPANoptosisferroptosisoxidative stressNADPH oxidase 2 |
| spellingShingle | Yuqiong Chen Bo Guan Jian Lu Xiaopei Yan Chao Huang Yuli Qiu Xinyan Li Xiangyu Sun Lin Chen Wei Li Wenjun Mao Zhongqi Sun Bin Xu Su Li Chao Chen Chao Chen Gypensapogenin I alleviates PANoptosis, ferroptosis, and oxidative stress in myocardial ischemic–reperfusion injury by targeting the NOX2/AMPK pathway Frontiers in Cell and Developmental Biology gypensapogenin I myocardial ischemia–reperfusion injury PANoptosis ferroptosis oxidative stress NADPH oxidase 2 |
| title | Gypensapogenin I alleviates PANoptosis, ferroptosis, and oxidative stress in myocardial ischemic–reperfusion injury by targeting the NOX2/AMPK pathway |
| title_full | Gypensapogenin I alleviates PANoptosis, ferroptosis, and oxidative stress in myocardial ischemic–reperfusion injury by targeting the NOX2/AMPK pathway |
| title_fullStr | Gypensapogenin I alleviates PANoptosis, ferroptosis, and oxidative stress in myocardial ischemic–reperfusion injury by targeting the NOX2/AMPK pathway |
| title_full_unstemmed | Gypensapogenin I alleviates PANoptosis, ferroptosis, and oxidative stress in myocardial ischemic–reperfusion injury by targeting the NOX2/AMPK pathway |
| title_short | Gypensapogenin I alleviates PANoptosis, ferroptosis, and oxidative stress in myocardial ischemic–reperfusion injury by targeting the NOX2/AMPK pathway |
| title_sort | gypensapogenin i alleviates panoptosis ferroptosis and oxidative stress in myocardial ischemic reperfusion injury by targeting the nox2 ampk pathway |
| topic | gypensapogenin I myocardial ischemia–reperfusion injury PANoptosis ferroptosis oxidative stress NADPH oxidase 2 |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2025.1623846/full |
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