FGF21 inhibits ferroptosis caused by mitochondrial damage to promote the repair of peripheral nerve injury
Introduction Ferroptosis is a new type of cell death characterized by lipid peroxidation and iron dependency, representing an emerging disease regulation mechanism. The limited understanding of ferroptosis in peripheral nerve injury (PNI) complicates the management of such injuries. Mitochondrial dy...
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Frontiers Media S.A.
2024-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1358646/full |
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| author | Yao Yan Yao Yan Yao Yan Xinyu Ran Xinyu Ran Zihan Zhou Zihan Zhou Yuting Gu Yuting Gu Yuting Gu Rendu Wang Rendu Wang Chuanqi Qiu Chuanqi Qiu Yinuo Sun Yinuo Sun Jifeng Wang Jifeng Wang Jian Xiao Jian Xiao Jian Xiao Yingfeng Lu Yingfeng Lu Jian Wang Jian Wang Jian Wang |
| author_facet | Yao Yan Yao Yan Yao Yan Xinyu Ran Xinyu Ran Zihan Zhou Zihan Zhou Yuting Gu Yuting Gu Yuting Gu Rendu Wang Rendu Wang Chuanqi Qiu Chuanqi Qiu Yinuo Sun Yinuo Sun Jifeng Wang Jifeng Wang Jian Xiao Jian Xiao Jian Xiao Yingfeng Lu Yingfeng Lu Jian Wang Jian Wang Jian Wang |
| author_sort | Yao Yan |
| collection | DOAJ |
| description | Introduction Ferroptosis is a new type of cell death characterized by lipid peroxidation and iron dependency, representing an emerging disease regulation mechanism. The limited understanding of ferroptosis in peripheral nerve injury (PNI) complicates the management of such injuries. Mitochondrial dysfunction, which contributes to ferroptosis, further exacerbates the challenges of peripheral nerve repairMethodsIn this study, we established an in vitro model of Schwann cells model treated with TBHP and an in vivo sciatic nerve crush injury model in rats. These models were used to investigate the effects of fibroblast growth factor 21 (FGF21) on PNI, both in vitro and in vivo, and to explore the potential mechanisms linking injury-induced ferroptosis and mitochondrial dysfunction.Results Our findings reveal that PNI triggers abnormal accumulation of lipid reactive oxygen species (ROS) and inactivates mitochondrial respiratory chain complex III, leading to mitochondrial dysfunction. This dysfunction catalyzes the oxidation of excessive polyunsaturated fatty acids, resulting in antioxidant imbalance and loss of ferroptosis suppressor protein 1 (FSP1), which drives lipid peroxidation. Additionally, irregular iron metabolism, defective mitophagy, and other factors contribute to the induction of ferroptosis. Importantly, we found that FGF21 attenuates the abnormal accumulation of lipid ROS, restores mitochondrial function, and suppresses ferroptosis, thus promoting PNI repair. Notably, glutathione peroxidase 4 (GPX4), a downstream target of nuclear factor E2-related factor 2 (Nrf2), and the ERK/Nrf2 pathway are involved in the regulation of ferroptosis by FGF21.ConclusionFGF21 promotes peripheral nerve repair by inhibiting ferroptosis caused by mitochondrial dysfunction. Therefore, targeting mitochondria and ferroptosis represents a promising therapeutic strategy for effective PNI repair. |
| format | Article |
| id | doaj-art-ac4636f726834d7dbb308db92682ffdb |
| institution | OA Journals |
| issn | 1663-9812 |
| language | English |
| publishDate | 2024-09-01 |
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| spelling | doaj-art-ac4636f726834d7dbb308db92682ffdb2025-08-20T02:05:07ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-09-011510.3389/fphar.2024.13586461358646FGF21 inhibits ferroptosis caused by mitochondrial damage to promote the repair of peripheral nerve injuryYao Yan0Yao Yan1Yao Yan2Xinyu Ran3Xinyu Ran4Zihan Zhou5Zihan Zhou6Yuting Gu7Yuting Gu8Yuting Gu9Rendu Wang10Rendu Wang11Chuanqi Qiu12Chuanqi Qiu13Yinuo Sun14Yinuo Sun15Jifeng Wang16Jifeng Wang17Jian Xiao18Jian Xiao19Jian Xiao20Yingfeng Lu21Yingfeng Lu22Jian Wang23Jian Wang24Jian Wang25Department of Wound Repair, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaCixi Biomedical Research Institute, Wenzhou Medical University, Wenzhou, Zhejiang, ChinaWenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Wound Repair, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaWenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Wound Repair, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaWenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Wound Repair, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaCixi Biomedical Research Institute, Wenzhou Medical University, Wenzhou, Zhejiang, ChinaWenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Wound Repair, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaWenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Wound Repair, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaWenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Wound Repair, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaWenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Wound Repair, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaWenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Wound Repair, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaCixi Biomedical Research Institute, Wenzhou Medical University, Wenzhou, Zhejiang, ChinaWenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Wound Repair, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaWenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Wound Repair, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaCixi Biomedical Research Institute, Wenzhou Medical University, Wenzhou, Zhejiang, ChinaWenzhou Medical University, Wenzhou, Zhejiang, ChinaIntroduction Ferroptosis is a new type of cell death characterized by lipid peroxidation and iron dependency, representing an emerging disease regulation mechanism. The limited understanding of ferroptosis in peripheral nerve injury (PNI) complicates the management of such injuries. Mitochondrial dysfunction, which contributes to ferroptosis, further exacerbates the challenges of peripheral nerve repairMethodsIn this study, we established an in vitro model of Schwann cells model treated with TBHP and an in vivo sciatic nerve crush injury model in rats. These models were used to investigate the effects of fibroblast growth factor 21 (FGF21) on PNI, both in vitro and in vivo, and to explore the potential mechanisms linking injury-induced ferroptosis and mitochondrial dysfunction.Results Our findings reveal that PNI triggers abnormal accumulation of lipid reactive oxygen species (ROS) and inactivates mitochondrial respiratory chain complex III, leading to mitochondrial dysfunction. This dysfunction catalyzes the oxidation of excessive polyunsaturated fatty acids, resulting in antioxidant imbalance and loss of ferroptosis suppressor protein 1 (FSP1), which drives lipid peroxidation. Additionally, irregular iron metabolism, defective mitophagy, and other factors contribute to the induction of ferroptosis. Importantly, we found that FGF21 attenuates the abnormal accumulation of lipid ROS, restores mitochondrial function, and suppresses ferroptosis, thus promoting PNI repair. Notably, glutathione peroxidase 4 (GPX4), a downstream target of nuclear factor E2-related factor 2 (Nrf2), and the ERK/Nrf2 pathway are involved in the regulation of ferroptosis by FGF21.ConclusionFGF21 promotes peripheral nerve repair by inhibiting ferroptosis caused by mitochondrial dysfunction. Therefore, targeting mitochondria and ferroptosis represents a promising therapeutic strategy for effective PNI repair.https://www.frontiersin.org/articles/10.3389/fphar.2024.1358646/fullperipheral nerve injuryferroptosismitochondriafibroblast growth factor 21 (FGF21)schwann cellROS |
| spellingShingle | Yao Yan Yao Yan Yao Yan Xinyu Ran Xinyu Ran Zihan Zhou Zihan Zhou Yuting Gu Yuting Gu Yuting Gu Rendu Wang Rendu Wang Chuanqi Qiu Chuanqi Qiu Yinuo Sun Yinuo Sun Jifeng Wang Jifeng Wang Jian Xiao Jian Xiao Jian Xiao Yingfeng Lu Yingfeng Lu Jian Wang Jian Wang Jian Wang FGF21 inhibits ferroptosis caused by mitochondrial damage to promote the repair of peripheral nerve injury Frontiers in Pharmacology peripheral nerve injury ferroptosis mitochondria fibroblast growth factor 21 (FGF21) schwann cell ROS |
| title | FGF21 inhibits ferroptosis caused by mitochondrial damage to promote the repair of peripheral nerve injury |
| title_full | FGF21 inhibits ferroptosis caused by mitochondrial damage to promote the repair of peripheral nerve injury |
| title_fullStr | FGF21 inhibits ferroptosis caused by mitochondrial damage to promote the repair of peripheral nerve injury |
| title_full_unstemmed | FGF21 inhibits ferroptosis caused by mitochondrial damage to promote the repair of peripheral nerve injury |
| title_short | FGF21 inhibits ferroptosis caused by mitochondrial damage to promote the repair of peripheral nerve injury |
| title_sort | fgf21 inhibits ferroptosis caused by mitochondrial damage to promote the repair of peripheral nerve injury |
| topic | peripheral nerve injury ferroptosis mitochondria fibroblast growth factor 21 (FGF21) schwann cell ROS |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1358646/full |
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