Liraglutide and GLP-1(9–37) alleviated hepatic ischemia-reperfusion injury by inhibiting ferroptosis via GSK3β/Nrf2 pathway and SMAD159/Hepcidin/FTH pathway
Ferroptosis plays a pivotal role in the pathogenesis of ischemia-reperfusion injury (IRI). Liraglutide, as a GLP-1 receptor (GLP-1R) agonist, has exhibited extensive biological effects beyond its hypoglycemic action. Recent studies have shed light on the regulatory influence of Liraglutide on ferrop...
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Elsevier
2025-02-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231724004464 |
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| author | Chenqi Lu Cong Xu Shanglin Li Haiqiang Ni Jun Yang |
| author_facet | Chenqi Lu Cong Xu Shanglin Li Haiqiang Ni Jun Yang |
| author_sort | Chenqi Lu |
| collection | DOAJ |
| description | Ferroptosis plays a pivotal role in the pathogenesis of ischemia-reperfusion injury (IRI). Liraglutide, as a GLP-1 receptor (GLP-1R) agonist, has exhibited extensive biological effects beyond its hypoglycemic action. Recent studies have shed light on the regulatory influence of Liraglutide on ferroptosis, yet the precise underlying mechanism remains elusive. GLP-1(9–37), as a metabolite of GLP-1, has a low affinity to GLP-1R. Its effect on ferroptosis remains unknown. In this study, we investigated the effects of Liraglutide and GLP-1(9–37) on the ferroptosis during hepatic ischemia-repferfusion (I/R), as well as the underlying specific mechanisms. We found that the administration of Liraglutide alleviated I/R-induced liver injury with less iron accumulation and lower lipid peroxidation, which was not entirely dependent on the presence of GLP-1R. Similarly, GLP-1(9–37) also exhibited these effects. Besides, both of them increased GPX4 expression and decreased COX2 expression. These effects were reversed by a High-Iron Diet. In vitro study showed similar results. In mechanism study, we found that both Liraglutide and GLP-1(9–37) treatment promoted the nuclear translocation of Nrf2 by inhibiting GSK-3β, thereby reducing lipid peroxides. Furthermore, they increased FTH and FTL expression via the SMAD159/Hepcidin pathway, which contributed to the decreased iron accumulation. In conclusion, this study determined that both Liraglutide and GLP-1(9–37) alleviated hepatic ischemia-reperfusion injury (HIRI) by suppressing ferroptosis via the activation of the GSK3β/Nrf2 pathway and the SMAD159/Hepcidin/FTH pathway. |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
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| series | Redox Biology |
| spelling | doaj-art-0c4be67c717943f9b0ee30cb367a3a052025-01-14T04:12:11ZengElsevierRedox Biology2213-23172025-02-0179103468Liraglutide and GLP-1(9–37) alleviated hepatic ischemia-reperfusion injury by inhibiting ferroptosis via GSK3β/Nrf2 pathway and SMAD159/Hepcidin/FTH pathwayChenqi Lu0Cong Xu1Shanglin Li2Haiqiang Ni3Jun Yang4Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, ChinaDivision of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of General Surgery, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China; Corresponding author. Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China; Corresponding author. Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.Ferroptosis plays a pivotal role in the pathogenesis of ischemia-reperfusion injury (IRI). Liraglutide, as a GLP-1 receptor (GLP-1R) agonist, has exhibited extensive biological effects beyond its hypoglycemic action. Recent studies have shed light on the regulatory influence of Liraglutide on ferroptosis, yet the precise underlying mechanism remains elusive. GLP-1(9–37), as a metabolite of GLP-1, has a low affinity to GLP-1R. Its effect on ferroptosis remains unknown. In this study, we investigated the effects of Liraglutide and GLP-1(9–37) on the ferroptosis during hepatic ischemia-repferfusion (I/R), as well as the underlying specific mechanisms. We found that the administration of Liraglutide alleviated I/R-induced liver injury with less iron accumulation and lower lipid peroxidation, which was not entirely dependent on the presence of GLP-1R. Similarly, GLP-1(9–37) also exhibited these effects. Besides, both of them increased GPX4 expression and decreased COX2 expression. These effects were reversed by a High-Iron Diet. In vitro study showed similar results. In mechanism study, we found that both Liraglutide and GLP-1(9–37) treatment promoted the nuclear translocation of Nrf2 by inhibiting GSK-3β, thereby reducing lipid peroxides. Furthermore, they increased FTH and FTL expression via the SMAD159/Hepcidin pathway, which contributed to the decreased iron accumulation. In conclusion, this study determined that both Liraglutide and GLP-1(9–37) alleviated hepatic ischemia-reperfusion injury (HIRI) by suppressing ferroptosis via the activation of the GSK3β/Nrf2 pathway and the SMAD159/Hepcidin/FTH pathway.http://www.sciencedirect.com/science/article/pii/S2213231724004464LiraglutideIschemia-reperfusion injuryGLP-1(9–37)Ferroptosis |
| spellingShingle | Chenqi Lu Cong Xu Shanglin Li Haiqiang Ni Jun Yang Liraglutide and GLP-1(9–37) alleviated hepatic ischemia-reperfusion injury by inhibiting ferroptosis via GSK3β/Nrf2 pathway and SMAD159/Hepcidin/FTH pathway Redox Biology Liraglutide Ischemia-reperfusion injury GLP-1(9–37) Ferroptosis |
| title | Liraglutide and GLP-1(9–37) alleviated hepatic ischemia-reperfusion injury by inhibiting ferroptosis via GSK3β/Nrf2 pathway and SMAD159/Hepcidin/FTH pathway |
| title_full | Liraglutide and GLP-1(9–37) alleviated hepatic ischemia-reperfusion injury by inhibiting ferroptosis via GSK3β/Nrf2 pathway and SMAD159/Hepcidin/FTH pathway |
| title_fullStr | Liraglutide and GLP-1(9–37) alleviated hepatic ischemia-reperfusion injury by inhibiting ferroptosis via GSK3β/Nrf2 pathway and SMAD159/Hepcidin/FTH pathway |
| title_full_unstemmed | Liraglutide and GLP-1(9–37) alleviated hepatic ischemia-reperfusion injury by inhibiting ferroptosis via GSK3β/Nrf2 pathway and SMAD159/Hepcidin/FTH pathway |
| title_short | Liraglutide and GLP-1(9–37) alleviated hepatic ischemia-reperfusion injury by inhibiting ferroptosis via GSK3β/Nrf2 pathway and SMAD159/Hepcidin/FTH pathway |
| title_sort | liraglutide and glp 1 9 37 alleviated hepatic ischemia reperfusion injury by inhibiting ferroptosis via gsk3β nrf2 pathway and smad159 hepcidin fth pathway |
| topic | Liraglutide Ischemia-reperfusion injury GLP-1(9–37) Ferroptosis |
| url | http://www.sciencedirect.com/science/article/pii/S2213231724004464 |
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