Xu Zi-Han, Xie Ming-Min, Xie Chun-Lan, Yang Xian-Wen, Wang Jun-Song
Center for Molecular Metabolism, School of Environmental and Biological Engineering, Nanjing University of Science and Technology, 200 Xiaolingwei Street, Nanjing 210094, China.
School of Basic Medicine and Life Science, Hainan Academy of Medical Sciences, Hainan Medical University, 3 Xueyuan Road, Haikou 571199, China.
Mar Drugs. 2025 Jan 20;23(1):49. doi: 10.3390/md23010049.
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 () as a compound with anti-inflammatory and ferroptosis-inhibiting effects. Using LPS-induced microglial inflammation and RSL3-induced neuronal ferroptosis models, we found that targets TLR4 to provide neuroprotection. Molecular docking studies revealed that inhibits TLR4 activation by occupying the hydrophobic pocket at the TLR4-MD2 binding site. Additionally, suppresses TLR4, reducing p38 MAPK phosphorylation, and inhibits ferroptosis by decreasing lipid peroxidation and modulating mitochondrial membrane potential. Metabolomic analysis showed that 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 () 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.
神经炎症和神经元细胞死亡是老年人死亡的主要原因，也是各种神经退行性疾病的基础。这些疾病涉及复杂的病理生理机制，包括炎症反应、氧化应激和铁死亡。源自深海真菌的化合物毒性低且具有强大的神经保护作用，为药物开发提供了一个有前景的来源。在本研究中，我们从深海来源的真菌中分离出44种天然产物，并鉴定出异双环氧木脂素（）是一种具有抗炎和抑制铁死亡作用的化合物。使用脂多糖诱导的小胶质细胞炎症和RSL3诱导的神经元铁死亡模型，我们发现 靶向Toll样受体4（TLR4）以提供神经保护。分子对接研究表明， 通过占据TLR4-MD2结合位点的疏水口袋来抑制TLR4激活。此外， 抑制TLR4，降低p38丝裂原活化蛋白激酶（MAPK）的磷酸化，并通过减少脂质过氧化和调节线粒体膜电位来抑制铁死亡。代谢组学分析表明， 可挽救由RSL3诱导的多种代谢途径的改变，并提高抗氧化代谢物的水平，包括谷氨酰胺、谷氨酸和谷胱甘肽。总之，我们的结果表明，异双环氧木脂素（）在神经细胞中靶向TLR4以减轻炎症并抑制p38 MAPK磷酸化，同时调节代谢途径，主要是谷胱甘肽合成，以提供抗氧化作用并预防神经元中的铁死亡。
