Cells rely on the endoplasmic reticulum (ER) to fold and assemble newly synthesized transmembrane and secretory proteins — essential for cellular structure–function and for both intracellular and intercellular communication. To ensure the operative fidelity of the ER, eukaryotic cells leverage the unfolded protein response (UPR) — a stress-sensing and signalling network that maintains homeostasis by rebalancing the biosynthetic capacity of the ER according to need. The metazoan UPR can also redirect signalling from cytoprotective adaptation to programmed cell death if homeostasis restoration fails. As such, the UPR benefits multicellular organisms by preserving optimally functioning cells while removing damaged ones. Nevertheless, dysregulation of the UPR can be harmful. In this Review, we discuss the UPR and its regulatory processes as a paradigm in health and disease. We highlight important recent advances in molecular and mechanistic understanding of the UPR that enable greater precision in designing and developing innovative strategies to harness its potential for therapeutic gain. We underscore the rheostatic character of the UPR, its contextual nature and critical open questions for its further elucidation.

细胞依靠内质网 （ER） 折叠和组装新合成的跨膜和分泌蛋白，这对细胞结构功能以及细胞内和细胞间通讯至关重要。为了确保 ER 的运作保真度，真核细胞利用未折叠蛋白反应 （UPR） — 一种压力感应和信号网络，通过根据需要重新平衡 ER 的生物合成能力来维持体内平衡。如果稳态恢复失败，后生动物 UPR 还可以将信号从细胞保护性适应重定向到程序性细胞死亡。因此，UPR 通过保留功能最佳的细胞同时去除受损的细胞，使多细胞生物受益。然而，普遍定期审议的失调可能是有害的。在本综述中，我们讨论了普遍定期审议及其监管过程作为健康和疾病的范式。我们强调了对 UPR 的分子和机制理解方面的最新重要进展，这些进展使得在设计和开发创新策略以利用其治疗收益的潜力方面具有更高的精度。我们强调了普遍定期审议的流变特性、其背景性质和需要进一步阐明的关键开放性问题。