Bioinformatics analysis combined with experimental validation reveals the novel mechanisms of multi-targets of dapagliflozin attenuating diabetic liver injury
ObjectiveDiabetic liver injury, a chronic complication of diabetes mellitus (DM), has been extensively documented. Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, has shown significant therapeutic benefits in clinical trials for the management of diabetes However, the specific me...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2025.1519153/full |
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| author | Pengyu Wang Pengyu Wang Zhen Sun Qing Lan Qing Lan Qing Lan Shuo Zhang Shuo Zhang Yan Song Yan Song Leiming Yang Leiming Yang Mi Chen Jianfen Shen Qi Huang Qi Huang Youzhi Zhang Youzhi Zhang |
| author_facet | Pengyu Wang Pengyu Wang Zhen Sun Qing Lan Qing Lan Qing Lan Shuo Zhang Shuo Zhang Yan Song Yan Song Leiming Yang Leiming Yang Mi Chen Jianfen Shen Qi Huang Qi Huang Youzhi Zhang Youzhi Zhang |
| author_sort | Pengyu Wang |
| collection | DOAJ |
| description | ObjectiveDiabetic liver injury, a chronic complication of diabetes mellitus (DM), has been extensively documented. Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, has shown significant therapeutic benefits in clinical trials for the management of diabetes However, the specific mechanism on the treatment of diabetic liver injury with dapagliflozin is not fully understood. Therefore, this study aims to further explore the potential mechanism of dapagliflozin on diabetic liver injury based on bioinformatics analysis and experimental verification.MethodsDiabetic liver injury was induced by a high-fat diet combined with STZ in mice. Biochemical kit detection and H&E staining were used to observe lipid aggregation and oxidative stress in liver tissue. Moreover, the expression of inflammatory and apoptosis-related factors was detected using western blotting (WB) and quantitative polymerase chain reaction (qPCR). Subsequently, differential expressions genes analysis, weighted gene co-expression network analysis (WGCNA), molecular docking, as well as molecular dynamics was conducted based on the Gene Expression Omnibus (GEO) and pharmacology databases. Finally, WB and qPCR were performed to validate the mechanism of dapagliflozin on diabetic liver injury in vivo and in vitro.ResultsDapagliflozin alleviated diabetic liver injury by decreasing lipid deposition, oxidative stress levels, the inflammatary and apoptosis-related proteins and mRNA levels, while it also reducing blood glucose. Mechanically, 78 overlapping genes of dapagliflozin and diabetic liver injury were obtained. Notably, Mapk3, Mapk1, Ikbkb, and Nfkb1 as the hub genes involved in dapagliflozin attenuating diabetic liver injury were identified, and dapagliflozin exhibited better affinity with these proteins. Moreover, dapagliflozin inhibited the elevated protein (genes) levels of ERK1/2 (Mapk3, Mapk1), IKKβ(Ikbkb), and NF-κB (Nfkb1), which are induced by diabetic liver injury, as confirmed by both in vivo and in vitro experiments.ConclusionDapagliflozin ameliorated diabetic liver injury by inhibiting the ERK/IKKβ/NF-κB signalling pathway, as demonstrated by bioinformatics analysis combined with in vivo and in vitro experiments. |
| format | Article |
| id | doaj-art-eaca2bde90ca437f8d1459d5a6ace544 |
| institution | DOAJ |
| issn | 1664-2392 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj-art-eaca2bde90ca437f8d1459d5a6ace5442025-08-20T02:58:26ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922025-05-011610.3389/fendo.2025.15191531519153Bioinformatics analysis combined with experimental validation reveals the novel mechanisms of multi-targets of dapagliflozin attenuating diabetic liver injuryPengyu Wang0Pengyu Wang1Zhen Sun2Qing Lan3Qing Lan4Qing Lan5Shuo Zhang6Shuo Zhang7Yan Song8Yan Song9Leiming Yang10Leiming Yang11Mi Chen12Jianfen Shen13Qi Huang14Qi Huang15Youzhi Zhang16Youzhi Zhang17Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning, ChinaHubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province, Hubei University of Science and Technology, Xianning, ChinaSchool of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaHubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning, ChinaHubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province, Hubei University of Science and Technology, Xianning, ChinaExperimental Animal Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, ChinaHubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning, ChinaHubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province, Hubei University of Science and Technology, Xianning, ChinaHubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning, ChinaHubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province, Hubei University of Science and Technology, Xianning, ChinaHubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning, ChinaHubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province, Hubei University of Science and Technology, Xianning, ChinaHubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning, ChinaDepartment of Central Laboratory, The Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, ChinaHubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning, ChinaHubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province, Hubei University of Science and Technology, Xianning, ChinaHubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning, ChinaHubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province, Hubei University of Science and Technology, Xianning, ChinaObjectiveDiabetic liver injury, a chronic complication of diabetes mellitus (DM), has been extensively documented. Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, has shown significant therapeutic benefits in clinical trials for the management of diabetes However, the specific mechanism on the treatment of diabetic liver injury with dapagliflozin is not fully understood. Therefore, this study aims to further explore the potential mechanism of dapagliflozin on diabetic liver injury based on bioinformatics analysis and experimental verification.MethodsDiabetic liver injury was induced by a high-fat diet combined with STZ in mice. Biochemical kit detection and H&E staining were used to observe lipid aggregation and oxidative stress in liver tissue. Moreover, the expression of inflammatory and apoptosis-related factors was detected using western blotting (WB) and quantitative polymerase chain reaction (qPCR). Subsequently, differential expressions genes analysis, weighted gene co-expression network analysis (WGCNA), molecular docking, as well as molecular dynamics was conducted based on the Gene Expression Omnibus (GEO) and pharmacology databases. Finally, WB and qPCR were performed to validate the mechanism of dapagliflozin on diabetic liver injury in vivo and in vitro.ResultsDapagliflozin alleviated diabetic liver injury by decreasing lipid deposition, oxidative stress levels, the inflammatary and apoptosis-related proteins and mRNA levels, while it also reducing blood glucose. Mechanically, 78 overlapping genes of dapagliflozin and diabetic liver injury were obtained. Notably, Mapk3, Mapk1, Ikbkb, and Nfkb1 as the hub genes involved in dapagliflozin attenuating diabetic liver injury were identified, and dapagliflozin exhibited better affinity with these proteins. Moreover, dapagliflozin inhibited the elevated protein (genes) levels of ERK1/2 (Mapk3, Mapk1), IKKβ(Ikbkb), and NF-κB (Nfkb1), which are induced by diabetic liver injury, as confirmed by both in vivo and in vitro experiments.ConclusionDapagliflozin ameliorated diabetic liver injury by inhibiting the ERK/IKKβ/NF-κB signalling pathway, as demonstrated by bioinformatics analysis combined with in vivo and in vitro experiments.https://www.frontiersin.org/articles/10.3389/fendo.2025.1519153/fulldapagliflozindiabetic liver injuryERK/IKKβ/NF-κB pathwaysbioinformaticsdata miningmetabolic disease |
| spellingShingle | Pengyu Wang Pengyu Wang Zhen Sun Qing Lan Qing Lan Qing Lan Shuo Zhang Shuo Zhang Yan Song Yan Song Leiming Yang Leiming Yang Mi Chen Jianfen Shen Qi Huang Qi Huang Youzhi Zhang Youzhi Zhang Bioinformatics analysis combined with experimental validation reveals the novel mechanisms of multi-targets of dapagliflozin attenuating diabetic liver injury Frontiers in Endocrinology dapagliflozin diabetic liver injury ERK/IKKβ/NF-κB pathways bioinformatics data mining metabolic disease |
| title | Bioinformatics analysis combined with experimental validation reveals the novel mechanisms of multi-targets of dapagliflozin attenuating diabetic liver injury |
| title_full | Bioinformatics analysis combined with experimental validation reveals the novel mechanisms of multi-targets of dapagliflozin attenuating diabetic liver injury |
| title_fullStr | Bioinformatics analysis combined with experimental validation reveals the novel mechanisms of multi-targets of dapagliflozin attenuating diabetic liver injury |
| title_full_unstemmed | Bioinformatics analysis combined with experimental validation reveals the novel mechanisms of multi-targets of dapagliflozin attenuating diabetic liver injury |
| title_short | Bioinformatics analysis combined with experimental validation reveals the novel mechanisms of multi-targets of dapagliflozin attenuating diabetic liver injury |
| title_sort | bioinformatics analysis combined with experimental validation reveals the novel mechanisms of multi targets of dapagliflozin attenuating diabetic liver injury |
| topic | dapagliflozin diabetic liver injury ERK/IKKβ/NF-κB pathways bioinformatics data mining metabolic disease |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2025.1519153/full |
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