Disturbances in the fatty acid lipidome are increasingly recognized as key drivers in the progression of various brain disorders. In this review article, we delve into the impact of Δ9 fatty acid desaturases, with a particular focus on stearoyl-CoA desaturase-1 (SCD1), within the setting of neuroinflammation, neurodegeneration, and brain repair. Over the past years, it was established that inhibition or deficiency of SCD1 not only suppresses neuroinflammation but also protects against neurodegeneration in conditions such as multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. This protective effect is achieved through different mechanisms including enhanced remyelination, reversal of synaptic and cognitive impairments, and mitigation of α-synuclein toxicity. Intriguingly, metabolic rerouting of fatty acids via SCD1 improves the pathology associated with X-linked adrenoleukodystrophy, suggesting context-dependent benign and harmful effects of SCD1 inhibition in the brain. Here, we summarize and discuss the cellular and molecular mechanisms underlying both the beneficial and detrimental effects of SCD1 in these neurological disorders. We explore commonalities and distinctions, shedding light on potential therapeutic challenges. Additionally, we touch upon future research directions that promise to deepen our understanding of SCD1 biology in brain disorders and potentially enhance the clinical utility of SCD1 inhibitors.

中文翻译：

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硬脂酰辅酶 A 去饱和酶-1：神经系统疾病的潜在治疗靶点


脂肪酸脂质组的紊乱越来越被认为是各种脑部疾病进展的关键驱动因素。在这篇综述文章中，我们深入探讨了 Δ9 脂肪酸去饱和酶的影响，特别关注硬脂酰辅酶 A 去饱和酶-1 （SCD1），在神经炎症、神经退行性和大脑修复的情况下。在过去的几年里，已经确定 SCD1 的抑制或缺乏不仅可以抑制神经炎症，还可以防止多发性硬化症、阿尔茨海默病和帕金森病等情况下的神经退行性变。这种保护作用是通过不同的机制实现的，包括增强髓鞘再生、逆转突触和认知障碍以及减轻 α-突触核蛋白毒性。有趣的是，通过 SCD1 的脂肪酸代谢重路由改善了与 X 连锁肾上腺脑白质营养不良相关的病理学，表明 SCD1 抑制在大脑中的环境依赖性良性和有害影响。在这里，我们总结并讨论了 SCD1 在这些神经系统疾病中有益和有害影响背后的细胞和分子机制。我们探讨了共同点和区别，阐明了潜在的治疗挑战。此外，我们还探讨了未来的研究方向，这些方向有望加深我们对脑部疾病中 SCD1 生物学的理解，并可能增强 SCD1 抑制剂的临床效用。