Huntington disease (HD) is a debilitating, currently incurable disease. Protein aggregation and metabolic deficits are pathological hallmarks but their link to neurodegeneration and symptoms remains debated.

Here, we summarize alterations in the levels of different sphingolipids in an attempt to characterize sphingolipid patterns specific to HD, an additional molecular hallmark of the disease. Based on the crucial role of sphingolipids in maintaining cellular homeostasis, the dynamic regulation of sphingolipids upon insults and their involvement in cellular stress responses, we hypothesize that maladaptations or blunted adaptations, especially following cellular stress due to reduced oxygen supply (hypoxia) contribute to the development of pathology in HD. We review how sphingolipids shape cellular energy metabolism and control proteostasis and suggest how these functions may fail in HD and in combination with additional insults. Finally, we evaluate the potential of improving cellular resilience in HD by conditioning approaches (improving the efficiency of cellular stress responses) and the role of sphingolipids therein.

Sphingolipid metabolism is crucial for cellular homeostasis and for adaptations following cellular stress, including hypoxia. Inadequate cellular management of hypoxic stress likely contributes to HD progression, and sphingolipids are potential mediators. Targeting sphingolipids and the hypoxic stress response are novel treatment strategies for HD.

亨廷顿病 (HD) 是一种使人衰弱的、目前无法治愈的疾病。蛋白质聚集和代谢缺陷是病理学标志，但它们与神经变性和症状的联系仍存在争议。

在这里，我们总结了不同鞘脂水平的变化，试图描述 HD 特有的鞘脂模式，这是该疾病的另一个分子标志。基于鞘脂在维持细胞稳态中的关键作用、鞘脂对损伤的动态调节及其参与细胞应激反应，我们假设适应不良或适应迟钝，尤其是在由于氧气供应减少（缺氧）引起的细胞应激后，会导致HD病理学的发展。我们回顾了鞘脂如何塑造细胞能量代谢和控制蛋白质稳态，并提出这些功能如何在 HD 以及与其他损伤相结合时失效。最后，

鞘脂代谢对于细胞稳态和细胞应激（包括缺氧）后的适应至关重要。缺氧应激的细胞管理不足可能会导致 HD 进展，而鞘脂是潜在的介质。靶向鞘脂和缺氧应激反应是 HD 的新型治疗策略。