The endoplasmic reticulum (ER) is a complex and dynamic organelle that regulates many cellular pathways, including protein synthesis, protein quality control, and lipid synthesis. When one or multiple ER roles are dysregulated and saturated, the ER enters a stress state, which, in turn, activates the highly conserved unfolded protein response (UPR). By sensing the accumulation of unfolded proteins or lipid bilayer stress (LBS) at the ER, the UPR triggers pathways to restore ER homeostasis and eventually induces apoptosis if the stress remains unresolved. In recent years, it has emerged that the UPR works intimately with other cellular pathways to maintain lipid homeostasis at the ER, and so does at cellular levels. Lipid distribution, along with lipid anabolism and catabolism, are tightly regulated, in part, by the ER. Dysfunctional and overwhelmed lipid-related pathways, independently or in combination with ER stress, can have reciprocal effects on other cellular functions, contributing to the development of diseases. In this review, we summarize the current understanding of the UPR in response to proteotoxic stress and LBS and the breadth of the functions mitigated by the UPR in different tissues and in the context of diseases.

内质网 (ER) 是一种复杂且动态的细胞器，可调节许多细胞通路，包括蛋白质合成、蛋白质质量控​​制和脂质合成。当一个或多个 ER 角色失调和饱和时，ER 进入应激状态，进而激活高度保守的未折叠蛋白反应 (UPR)。通过感知 ER 上未折叠蛋白或脂质双层应激 (LBS) 的积累，UPR 触发恢复 ER 稳态的途径，如果应激仍未解决，最终会诱导细胞凋亡。近年来，已经发现 UPR 与其他细胞通路密切合作，以维持 ER 的脂质稳态，在细胞水平也是如此。脂质分布以及脂质合成代谢和分解代谢在一定程度上受到 ER 的严格调节。功能失调和不堪重负的脂质相关通路，独立地或与 ER 应激结合，可以对其他细胞功能产生相互影响，从而导致疾病的发展。在这篇综述中，我们总结了目前对 UPR 响应蛋白毒性应激和 LBS 的理解，以及 UPR 在不同组织和疾病背景下减轻的功能范围。