创伤性脑损伤后脂质代谢重编程分子机制的研究进展

Research Progress on the Molecular Mechanisms of Lipid Metabolic Reprogramming Following Traumatic Brain Injury

摘要:

创伤性脑损伤(TBI)后继发性脑损伤的病理机制复杂，脂质代谢重编程作为新兴研究领域日益受到关注。本文系统综述了TBI后中枢神经系统脂质代谢网络的特征性改变，涵盖脂质代谢谱重构、脂肪酸氧化障碍、磷脂代谢紊乱及脂滴动态变化等病理生理学特征，重点阐述了脂质代谢重编程介导继发性损伤的分子机制：ACSL4介导的多不饱和脂肪酸磷脂重塑增加膜脂过氧化易感性，并在GPX4抗氧化防御受损时诱导神经元铁死亡；小胶质细胞脂质代谢重编程可促进其向促炎反应表型转换并放大神经炎症；星形胶质细胞与脑微血管内皮细胞的脂质代谢失衡加剧血脑屏障破坏及线粒体功能障碍。本文进一步总结了酰基辅酶A合成酶家族、GPX4抗氧化防御系统及核受体等关键调控分子，并评估了铁死亡抑制剂、代谢酶靶向调节剂及功能性生物材料等治疗策略的神经保护效果与转化前景。当前研究面临单细胞水平时空动态解析不足、细胞类型特异性机制不明及临床转化路径优化等挑战，未来需整合多组学技术与精准医学策略以实现脂质代谢网络的特异性调控。创伤性脑损伤(TBI)后继发性脑损伤的病理机制复杂，脂质代谢重编程作为新兴研究领域日益受到关注。本文系统综述了TBI后中枢神经系统脂质代谢网络的特征性改变，涵盖脂质代谢谱重构、脂肪酸氧化障碍、磷脂代谢紊乱及脂滴动态变化等病理生理学特征，重点阐述了脂质代谢重编程介导继发性损伤的分子机制：ACSL4介导的多不饱和脂肪酸磷脂重塑增加膜脂过氧化易感性，并在GPX4抗氧化防御受损时诱导神经元铁死亡；小胶质细胞脂质代谢重编程可促进其向促炎反应表型转换并放大神经炎症；星形胶质细胞与脑微血管内皮细胞的脂质代谢失衡加剧血脑屏障破坏及线粒体功能障碍。本文进一步总结了酰基辅酶A合成酶家族、GPX4抗氧化防御系统及核受体等关键调控分子，并评估了铁死亡抑制剂、代谢酶靶向调节剂及功能性生物材料等治疗策略的神经保护效果与转化前景。当前研究面临单细胞水平时空动态解析不足、细胞类型特异性机制不明及临床转化路径优化等挑战，未来需整合多组学技术与精准医学策略以实现脂质代谢网络的特异性调控。

Abstract:

The pathophysiological mechanisms underlying secondary brain injury following traumatic brain injury (TBI) are complex, with lipid metabolic reprogramming emerging as an increasingly prominent area of research. This review systematically summarizes the characteristic alterations in the central nervous system lipid metabolic network after TBI, encompassing pathological and physiological features such as the reconstruction of the lipid metabolome, impaired fatty acid oxidation, phospholipid metabolism disorders, and dynamic changes in lipid droplets. It further elucidates the molecular mechanisms by which lipid metabolic reprogramming mediates secondary injury: ACSL4-mediated remodeling of polyunsaturated fatty acids into phospholipids increases susceptibility to membrane lipid peroxidation, inducing neuronal ferroptosis when GPX4-mediated antioxidant defense is compromised; microglial lipid metabolic reprogramming promotes polarization toward a neuroinflammatory phenotype; and imbalanced lipid metabolism in astrocytes and brain microvascular endothelial cells exacerbates blood-brain barrier disruption and mitochondrial dysfunction. This article also summarizes key regulatory molecules, including the acyl-CoA synthetase family, the GPX4 antioxidant defense system, and nuclear receptors, while evaluating the neuroprotective effects and translational prospects of therapeutic strategies such as ferroptosis inhibitors, targeted modulators of metabolic enzymes, and functional biomaterials. Current research faces challenges including insufficient spatiotemporal dynamic resolution at the single-cell level, unclear cell-type-specific mechanisms, and the need to optimize clinical translation pathways. Future efforts must integrate multi-omics technologies with precision medicine strategies to achieve specific regulation of the lipid metabolic network.