THSG counteracts microglial glycolytic reprogramming and neuronal necroptosis both in vivo and in vitro under conditions of neuroinflammation
Abstract Microglial activation, driven by a metabolic shift towards aerobic glycolysis, is implicated in neuroinflammation and neurological disorders like depression. THSG (2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside), derived from Polygonum multiflorum, exhibits anti-inflammatory and neuroprote...
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Nature Portfolio
2025-07-01
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| Online Access: | https://doi.org/10.1038/s41598-025-05994-y |
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| author | Zhe Guo Sijia Zhong Jinpeng Bai Xiuyuan Lang Minmin Cao Yang Hu Xiaoyan Qin Yingyu Sun |
| author_facet | Zhe Guo Sijia Zhong Jinpeng Bai Xiuyuan Lang Minmin Cao Yang Hu Xiaoyan Qin Yingyu Sun |
| author_sort | Zhe Guo |
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| description | Abstract Microglial activation, driven by a metabolic shift towards aerobic glycolysis, is implicated in neuroinflammation and neurological disorders like depression. THSG (2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside), derived from Polygonum multiflorum, exhibits anti-inflammatory and neuroprotective properties, but its mechanisms, particularly its impact on microglial metabolism, are largely unexplored. Using a LPS-induced mouse model of neuroinflammation, we observed that THSG significantly ameliorated depression-like behaviors. It suppressed pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6, iNOS), inhibited microglial activation, and reduced key necroptosis markers (phosphorylated RIPK1, RIPK3, and MLKL) in the hippocampus. Importantly, THSG effectively suppressed LPS-induced activation of the glycolytic pathway in the hippocampus, as evidenced by increased ATP levels, decreased lactate levels, reduced activity of key glycolytic enzymes, and decreased expression of PKM2 and HIF-1α, critical players in microglial glycolysis. Further in vitro studies with BV2 microglial cells confirmed that THSG significantly suppressed glycolytic enhancement, promoting a metabolic shift towards oxidative phosphorylation, thus inhibiting inflammatory activation of microglia. Co-culture experiments of BV2 cells and SH-SY5Y cells further corroborated the in vivo findings, demonstrating that THSG mitigated inflammation-induced necroptosis in SH-SY5Y neurons by reducing phosphorylation of RIPK1, RIPK3, and MLKL, thus protecting neurons from damage. Our results highlight the potential of THSG as a therapeutic agent for neuroinflammatory disorders by modulating microglial metabolic reprogramming and inhibiting neuronal necroptosis. |
| format | Article |
| id | doaj-art-68c60f6de04b46de934a5e11f003f903 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-68c60f6de04b46de934a5e11f003f9032025-08-20T03:38:16ZengNature PortfolioScientific Reports2045-23222025-07-0115111410.1038/s41598-025-05994-yTHSG counteracts microglial glycolytic reprogramming and neuronal necroptosis both in vivo and in vitro under conditions of neuroinflammationZhe Guo0Sijia Zhong1Jinpeng Bai2Xiuyuan Lang3Minmin Cao4Yang Hu5Xiaoyan Qin6Yingyu Sun7The Emergency Department, The Third Affiliated Hospital of Guangxi Medical UniversityKhoury College of Computer Sciences, Northeastern University Seattle CampusKey Laboratory of Ecology and Environment in Minority Areas National Ethnic Affairs Commission, Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of ChinaDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve UniversityKey Laboratory of Ecology and Environment in Minority Areas National Ethnic Affairs Commission, Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of ChinaKey Laboratory of Ecology and Environment in Minority Areas National Ethnic Affairs Commission, Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of ChinaKey Laboratory of Ecology and Environment in Minority Areas National Ethnic Affairs Commission, Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of ChinaBeijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal UniversityAbstract Microglial activation, driven by a metabolic shift towards aerobic glycolysis, is implicated in neuroinflammation and neurological disorders like depression. THSG (2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside), derived from Polygonum multiflorum, exhibits anti-inflammatory and neuroprotective properties, but its mechanisms, particularly its impact on microglial metabolism, are largely unexplored. Using a LPS-induced mouse model of neuroinflammation, we observed that THSG significantly ameliorated depression-like behaviors. It suppressed pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6, iNOS), inhibited microglial activation, and reduced key necroptosis markers (phosphorylated RIPK1, RIPK3, and MLKL) in the hippocampus. Importantly, THSG effectively suppressed LPS-induced activation of the glycolytic pathway in the hippocampus, as evidenced by increased ATP levels, decreased lactate levels, reduced activity of key glycolytic enzymes, and decreased expression of PKM2 and HIF-1α, critical players in microglial glycolysis. Further in vitro studies with BV2 microglial cells confirmed that THSG significantly suppressed glycolytic enhancement, promoting a metabolic shift towards oxidative phosphorylation, thus inhibiting inflammatory activation of microglia. Co-culture experiments of BV2 cells and SH-SY5Y cells further corroborated the in vivo findings, demonstrating that THSG mitigated inflammation-induced necroptosis in SH-SY5Y neurons by reducing phosphorylation of RIPK1, RIPK3, and MLKL, thus protecting neurons from damage. Our results highlight the potential of THSG as a therapeutic agent for neuroinflammatory disorders by modulating microglial metabolic reprogramming and inhibiting neuronal necroptosis.https://doi.org/10.1038/s41598-025-05994-yTHSGNeuroinflammationMicrogliaMetabolic reprogrammingNecroptosisDepression |
| spellingShingle | Zhe Guo Sijia Zhong Jinpeng Bai Xiuyuan Lang Minmin Cao Yang Hu Xiaoyan Qin Yingyu Sun THSG counteracts microglial glycolytic reprogramming and neuronal necroptosis both in vivo and in vitro under conditions of neuroinflammation Scientific Reports THSG Neuroinflammation Microglia Metabolic reprogramming Necroptosis Depression |
| title | THSG counteracts microglial glycolytic reprogramming and neuronal necroptosis both in vivo and in vitro under conditions of neuroinflammation |
| title_full | THSG counteracts microglial glycolytic reprogramming and neuronal necroptosis both in vivo and in vitro under conditions of neuroinflammation |
| title_fullStr | THSG counteracts microglial glycolytic reprogramming and neuronal necroptosis both in vivo and in vitro under conditions of neuroinflammation |
| title_full_unstemmed | THSG counteracts microglial glycolytic reprogramming and neuronal necroptosis both in vivo and in vitro under conditions of neuroinflammation |
| title_short | THSG counteracts microglial glycolytic reprogramming and neuronal necroptosis both in vivo and in vitro under conditions of neuroinflammation |
| title_sort | thsg counteracts microglial glycolytic reprogramming and neuronal necroptosis both in vivo and in vitro under conditions of neuroinflammation |
| topic | THSG Neuroinflammation Microglia Metabolic reprogramming Necroptosis Depression |
| url | https://doi.org/10.1038/s41598-025-05994-y |
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