内质网 (ER) 对于蛋白质质量控​​制至关重要，其功能中断可能导致各种疾病。内质网应激会触发一种称为未折叠蛋白反应（UPR）的适应性反应，它可以恢复细胞稳态或诱导细胞死亡。褪黑激素是一种安全的多功能化合物，在控制 ER 应激方面显示出良好的前景，并且可能成为管理 UPR 的有价值的治疗剂。通过调节 ER 和线粒体功能，褪黑激素通过减少氧化应激、炎症和细胞凋亡来帮助维持细胞稳态。褪黑激素可以直接或间接干扰 ER 相关传感器和 UPR 下游靶标，影响细胞死亡、自噬、炎症、分子修复等。至关重要的是，这篇综述探讨了褪黑激素对各种疾病中内质网应激的机制作用，包括肝损伤、神经退行性疾病、生殖障碍、肺部疾病、心肌病、胰岛素抵抗、肾功能障碍和癌症。有趣的是，虽然它在大多数病理情况下减轻了内质网应激的负担，但它却可以矛盾地刺激癌细胞中的内质网应激，突出了它在细胞稳态中的复杂参与。由于使用体内和体外模型进行了大量成功的研究，因此必须继续进行临床试验，以充分探索褪黑激素在这些情况下的治疗潜力。© 2024 Wiley periodicals LLC。

The endoplasmic reticulum (ER) is crucial for protein quality control, and disruptions in its function can lead to various diseases. ER stress triggers an adaptive response called the unfolded protein response (UPR), which can either restore cellular homeostasis or induce cell death. Melatonin, a safe and multifunctional compound, shows promise in controlling ER stress and could be a valuable therapeutic agent for managing the UPR. By regulating ER and mitochondrial functions, melatonin helps maintain cellular homeostasis via reduction of oxidative stress, inflammation, and apoptosis. Melatonin can directly or indirectly interfere with ER-associated sensors and downstream targets of the UPR, impacting cell death, autophagy, inflammation, molecular repair, among others. Crucially, this review explores the mechanistic role of melatonin on ER stress in various diseases including liver damage, neurodegeneration, reproductive disorders, pulmonary disease, cardiomyopathy, insulin resistance, renal dysfunction, and cancer. Interestingly, while it alleviates the burden of ER stress in most pathological contexts, it can paradoxically stimulate ER stress in cancer cells, highlighting its intricate involvement in cellular homeostasis. With numerous successful studies using in vivo and in vitro models, the continuation of clinical trials is imperative to fully explore melatonin's therapeutic potential in these conditions.© 2024 Wiley Periodicals LLC.