The endoplasmic reticulum (ER) is a cellular organelle that is physiologically responsible for protein folding, calcium homeostasis, and lipid biosynthesis. Pathological stimuli such as oxidative stress, ischemia, disruptions in calcium homeostasis, and increased production of normal and/or folding-defective proteins all contribute to the accumulation of misfolded proteins in the ER, causing ER stress. The adaptive response to ER stress is the activation of unfolded protein response (UPR), which affect a wide variety of cellular functions to maintain ER homeostasis or lead to apoptosis. Three different ER transmembrane sensors, including PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme-1 (IRE1), are responsible for initiating UPR. The UPR involves a variety of signal transduction pathways that reduce unfolded protein accumulation by boosting ER-resident chaperones, limiting protein translation, and accelerating unfolded protein degradation. ER is now acknowledged as a critical organelle in sensing dangers and determining cell life and death. On the other hand, UPR plays a critical role in the development and progression of several diseases such as cardiovascular diseases (CVD), metabolic disorders, chronic kidney diseases, neurological disorders, and cancer. Here, we critically analyze the most current knowledge of the master regulatory roles of ER stress particularly the PERK pathway as a conditional danger receptor, an organelle crosstalk regulator, and a regulator of protein translation. We highlighted that PERK is not only ER stress regulator by sensing UPR and ER stress but also a frontier sensor and direct senses for gut microbiota-generated metabolites. Our work also further highlighted the function of PERK as a central hub that leads to metabolic reprogramming and epigenetic modification which further enhanced inflammatory response and promoted trained immunity. Moreover, we highlighted the contribution of ER stress and PERK in the pathogenesis of several diseases such as cancer, CVD, kidney diseases, and neurodegenerative disorders. Finally, we discuss the therapeutic target of ER stress and PERK for cancer treatment and the potential novel therapeutic targets for CVD, metabolic disorders, and neurodegenerative disorders. Inhibition of ER stress, by the development of small molecules that target the PERK and UPR, represents a promising therapeutic strategy.

中文翻译：

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富含蛋白质的食物、海鲜和肠道微生物群可增强慢性疾病和癌症的免疫反应——将 PERK 作为慢性炎症性疾病、神经退行性疾病和癌症的新型治疗策略

内质网 (ER) 是一种细胞器，在生理上负责蛋白质折叠、钙稳态和脂质生物合成。氧化应激、缺血、钙稳态破坏以及正常和/或折叠缺陷蛋白产生增加等病理刺激都会导致错误折叠蛋白在内质网中积累，从而引起内质网应激。对内质网应激的适应性反应是未折叠蛋白反应（UPR）的激活，它影响多种细胞功能以维持内质网稳态或导致细胞凋亡。三种不同的 ER 跨膜传感器，包括 PKR 样 ER 激酶 (PERK)、激活转录因子 6 (ATF6) 和肌醇需求酶 1 (IRE1)，负责启动 UPR。UPR涉及多种信号转导途径，通过增强内质网驻留分子伴侣、限制蛋白质翻译和加速未折叠蛋白降解来减少未折叠蛋白积累。内质网现在被认为是感知危险和决定细胞生死的关键细胞器。另一方面，UPR在心血管疾病（CVD）、代谢紊乱、慢性肾脏疾病、神经系统疾病和癌症等多种疾病的发生和进展中发挥着关键作用。在这里，我们批判性地分析了有关 ER 应激主要调节作用的最新知识，特别是 PERK 通路作为条件危险受体、细胞器串扰调节器和蛋白质翻译调节器的知识。我们强调，PERK 不仅是通过感知 UPR 和 ER 应激的 ER 应激调节剂，而且还是一种前沿传感器和直接感知肠道微生物群产生的代谢物。我们的工作还进一步强调了 PERK 作为导致代谢重编程和表观遗传修饰的中心枢纽的功能，从而进一步增强炎症反应并促进训练有素的免疫力。此外，我们强调了 ER 应激和 PERK 在癌症、CVD、肾脏疾病和神经退行性疾病等多种疾病发病机制中的贡献。最后，我们讨论了 ER 应激和 PERK 在癌症治疗中的治疗靶点，以及 CVD、代谢性疾病和神经退行性疾病的潜在新治疗靶点。通过开发针对 PERK 和 UPR 的小分子来抑制 ER 应激是一种有前途的治疗策略。