Deep-Sea-Derived Isobisvertinol Targets TLR4 to Exhibit Neuroprotective Activity via Anti-Inflammatory and Ferroptosis-Inhibitory Effects
Neuroinflammation and neuronal cell death are leading causes of death in the elderly and underlie various neurodegenerative diseases. These diseases involve complex pathophysiological mechanisms, including inflammatory responses, oxidative stress, and ferroptosis. Compounds derived from deep-sea fun...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Marine Drugs |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1660-3397/23/1/49 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832588076689391616 |
|---|---|
| author | Zi-Han Xu Ming-Min Xie Chun-Lan Xie Xian-Wen Yang Jun-Song Wang |
| author_facet | Zi-Han Xu Ming-Min Xie Chun-Lan Xie Xian-Wen Yang Jun-Song Wang |
| author_sort | Zi-Han Xu |
| collection | DOAJ |
| description | Neuroinflammation and neuronal cell death are leading causes of death in the elderly and underlie various neurodegenerative diseases. These diseases involve complex pathophysiological mechanisms, including inflammatory responses, oxidative stress, and ferroptosis. Compounds derived from deep-sea fungi exhibit low toxicity and potent neuroprotective effects, offering a promising source for drug development. In this study, we isolated 44 natural products from deep-sea-derived fungi and identified isobisvertinol (<b>17</b>) as a compound with anti-inflammatory and ferroptosis-inhibiting effects. Using LPS-induced microglial inflammation and RSL3-induced neuronal ferroptosis models, we found that <b>17</b> targets TLR4 to provide neuroprotection. Molecular docking studies revealed that <b>17</b> inhibits TLR4 activation by occupying the hydrophobic pocket at the TLR4-MD2 binding site. Additionally, <b>17</b> suppresses TLR4, reducing p38 MAPK phosphorylation, and inhibits ferroptosis by decreasing lipid peroxidation and modulating mitochondrial membrane potential. Metabolomic analysis showed that <b>17</b> rescues alterations in multiple metabolic pathways induced by RSL3 and increases levels of antioxidant metabolites, including glutamine, glutamate, and glutathione. In summary, our results indicate that isobisvertinol (<b>17</b>) targets TLR4 in neural cells to reduce inflammation and inhibit p38 MAPK phosphorylation, while regulating metabolic pathways, mainly GSH synthesis, to provide antioxidant effects and prevent ferroptosis in neurons. |
| format | Article |
| id | doaj-art-9ba6fce8a2ee4d32b8e13ed5e8da1ed4 |
| institution | Kabale University |
| issn | 1660-3397 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj-art-9ba6fce8a2ee4d32b8e13ed5e8da1ed42025-01-24T13:39:37ZengMDPI AGMarine Drugs1660-33972025-01-012314910.3390/md23010049Deep-Sea-Derived Isobisvertinol Targets TLR4 to Exhibit Neuroprotective Activity via Anti-Inflammatory and Ferroptosis-Inhibitory EffectsZi-Han Xu0Ming-Min Xie1Chun-Lan Xie2Xian-Wen Yang3Jun-Song Wang4Center for Molecular Metabolism, School of Environmental and Biological Engineering, Nanjing University of Science and Technology, 200 Xiaolingwei Street, Nanjing 210094, ChinaKey Laboratory of Marine Genetic Resources, Third Institute of Oceanography, Ministry of Natural Resources, 184 Daxue Road, Xiamen 361005, ChinaSchool of Basic Medicine and Life Science, Hainan Academy of Medical Sciences, Hainan Medical University, 3 Xueyuan Road, Haikou 571199, ChinaSchool of Basic Medicine and Life Science, Hainan Academy of Medical Sciences, Hainan Medical University, 3 Xueyuan Road, Haikou 571199, ChinaCenter for Molecular Metabolism, School of Environmental and Biological Engineering, Nanjing University of Science and Technology, 200 Xiaolingwei Street, Nanjing 210094, ChinaNeuroinflammation and neuronal cell death are leading causes of death in the elderly and underlie various neurodegenerative diseases. These diseases involve complex pathophysiological mechanisms, including inflammatory responses, oxidative stress, and ferroptosis. Compounds derived from deep-sea fungi exhibit low toxicity and potent neuroprotective effects, offering a promising source for drug development. In this study, we isolated 44 natural products from deep-sea-derived fungi and identified isobisvertinol (<b>17</b>) as a compound with anti-inflammatory and ferroptosis-inhibiting effects. Using LPS-induced microglial inflammation and RSL3-induced neuronal ferroptosis models, we found that <b>17</b> targets TLR4 to provide neuroprotection. Molecular docking studies revealed that <b>17</b> inhibits TLR4 activation by occupying the hydrophobic pocket at the TLR4-MD2 binding site. Additionally, <b>17</b> suppresses TLR4, reducing p38 MAPK phosphorylation, and inhibits ferroptosis by decreasing lipid peroxidation and modulating mitochondrial membrane potential. Metabolomic analysis showed that <b>17</b> rescues alterations in multiple metabolic pathways induced by RSL3 and increases levels of antioxidant metabolites, including glutamine, glutamate, and glutathione. In summary, our results indicate that isobisvertinol (<b>17</b>) targets TLR4 in neural cells to reduce inflammation and inhibit p38 MAPK phosphorylation, while regulating metabolic pathways, mainly GSH synthesis, to provide antioxidant effects and prevent ferroptosis in neurons.https://www.mdpi.com/1660-3397/23/1/49marine natural productsmetabolomicsneuroprotectionanti-inflammatoryferroptosis inhibition |
| spellingShingle | Zi-Han Xu Ming-Min Xie Chun-Lan Xie Xian-Wen Yang Jun-Song Wang Deep-Sea-Derived Isobisvertinol Targets TLR4 to Exhibit Neuroprotective Activity via Anti-Inflammatory and Ferroptosis-Inhibitory Effects Marine Drugs marine natural products metabolomics neuroprotection anti-inflammatory ferroptosis inhibition |
| title | Deep-Sea-Derived Isobisvertinol Targets TLR4 to Exhibit Neuroprotective Activity via Anti-Inflammatory and Ferroptosis-Inhibitory Effects |
| title_full | Deep-Sea-Derived Isobisvertinol Targets TLR4 to Exhibit Neuroprotective Activity via Anti-Inflammatory and Ferroptosis-Inhibitory Effects |
| title_fullStr | Deep-Sea-Derived Isobisvertinol Targets TLR4 to Exhibit Neuroprotective Activity via Anti-Inflammatory and Ferroptosis-Inhibitory Effects |
| title_full_unstemmed | Deep-Sea-Derived Isobisvertinol Targets TLR4 to Exhibit Neuroprotective Activity via Anti-Inflammatory and Ferroptosis-Inhibitory Effects |
| title_short | Deep-Sea-Derived Isobisvertinol Targets TLR4 to Exhibit Neuroprotective Activity via Anti-Inflammatory and Ferroptosis-Inhibitory Effects |
| title_sort | deep sea derived isobisvertinol targets tlr4 to exhibit neuroprotective activity via anti inflammatory and ferroptosis inhibitory effects |
| topic | marine natural products metabolomics neuroprotection anti-inflammatory ferroptosis inhibition |
| url | https://www.mdpi.com/1660-3397/23/1/49 |
| work_keys_str_mv | AT zihanxu deepseaderivedisobisvertinoltargetstlr4toexhibitneuroprotectiveactivityviaantiinflammatoryandferroptosisinhibitoryeffects AT mingminxie deepseaderivedisobisvertinoltargetstlr4toexhibitneuroprotectiveactivityviaantiinflammatoryandferroptosisinhibitoryeffects AT chunlanxie deepseaderivedisobisvertinoltargetstlr4toexhibitneuroprotectiveactivityviaantiinflammatoryandferroptosisinhibitoryeffects AT xianwenyang deepseaderivedisobisvertinoltargetstlr4toexhibitneuroprotectiveactivityviaantiinflammatoryandferroptosisinhibitoryeffects AT junsongwang deepseaderivedisobisvertinoltargetstlr4toexhibitneuroprotectiveactivityviaantiinflammatoryandferroptosisinhibitoryeffects |