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<p>Peri-lesional microglia are particularly sensitive to traumatic brain injury (TBI)-induced disruption of brain lipid homeostasis. This disruption is characterized by elevated levels of acylcarnitines and phospholipids in acute lipidomic profiling, reflecting global lipid alterations. Under physiological conditions, microglial lipid processing involves fatty acid uptake, storage, and mitochondrial oxidation. However, following TBI, excessive fatty acid uptake promotes lipid droplet accumulation, mitochondrial stress, and pro-inflammatory activation. In this study, we investigated whether modulating this process confers therapeutic benefits. Trilobatin (Tri), a natural flavonoid glycoside with potent immunometabolic modulatory activity, markedly reduced neuroinflammation and neuropathological damage while improving motor and cognitive performance in a mouse model of TBI. Integrated transcriptomic and metabolomic analyses revealed that Tri reduced excessive mitochondrial lipid accumulation, alleviated mitochondrial damage, and inhibited mitochondrial DNA release, thereby blocking the TLR9/MyD88/P-P65 pro-inflammatory pathway. Further screening and validation identified that Tri downregulates the lipid transporter SLC27A3, limits excessive lipid uptake, and consequently alleviates microglial pro-inflammatory responses driven by lipid overload. Collectively, these findings establish a link between microglial lipid metabolism and inflammatory activation and support trilobatin as a promising therapeutic agent targeting metabolic-inflammatory crosstalk in acute neural injury.</p> Graphical Abstract <p></p>

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SLC27A3-dependent lipid metabolic reprogramming by trilobatin suppresses microglial mtDNA/TLR9-driven inflammatory activation in traumatic brain injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Hui-Wen Zhang,
  • Xue-Jie Wang,
  • Mao-Mao Chu,
  • Guang-Yuan Xing,
  • Kai Qiu,
  • Yu-Ge Zhang,
  • Wen-Feng Zhang,
  • Yu-Tong Zhang,
  • Xue Liu,
  • Lei Li,
  • Xiao-Wei Lu,
  • Xin-Xin Huang,
  • Lei-Yang Zhang,
  • Zhi-Yuan Zhang

摘要

Peri-lesional microglia are particularly sensitive to traumatic brain injury (TBI)-induced disruption of brain lipid homeostasis. This disruption is characterized by elevated levels of acylcarnitines and phospholipids in acute lipidomic profiling, reflecting global lipid alterations. Under physiological conditions, microglial lipid processing involves fatty acid uptake, storage, and mitochondrial oxidation. However, following TBI, excessive fatty acid uptake promotes lipid droplet accumulation, mitochondrial stress, and pro-inflammatory activation. In this study, we investigated whether modulating this process confers therapeutic benefits. Trilobatin (Tri), a natural flavonoid glycoside with potent immunometabolic modulatory activity, markedly reduced neuroinflammation and neuropathological damage while improving motor and cognitive performance in a mouse model of TBI. Integrated transcriptomic and metabolomic analyses revealed that Tri reduced excessive mitochondrial lipid accumulation, alleviated mitochondrial damage, and inhibited mitochondrial DNA release, thereby blocking the TLR9/MyD88/P-P65 pro-inflammatory pathway. Further screening and validation identified that Tri downregulates the lipid transporter SLC27A3, limits excessive lipid uptake, and consequently alleviates microglial pro-inflammatory responses driven by lipid overload. Collectively, these findings establish a link between microglial lipid metabolism and inflammatory activation and support trilobatin as a promising therapeutic agent targeting metabolic-inflammatory crosstalk in acute neural injury.

Graphical Abstract