Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.

中文翻译：

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蛋白酶体作为具有多种治疗潜力的药物靶标：切割边缘和非切割边缘。

泛素蛋白酶体系统 (UPS) 是一种适应性强且经过微调的系统，可在多种病理生理条件下维持蛋白质稳态网络。它的失调通常与人类疾病的发生和进展有关；因此，UPS 调制已成为开发癌症和神经退行性疾病等多种相关病理学治疗的有前景的新途径。2003 年 FDA 批准硼替佐米治疗复发/难治性多发性骨髓瘤后，临床对蛋白酶体抑制的兴趣大大增加，目前硼替佐米已用于一线治疗。此后，另外两种旨在克服硼替佐米耐药性的蛋白酶体抑制剂（卡非佐米和伊沙佐米）已被批准用于有治疗经验的患者，并且多种新型抑制剂目前正在进行临床前和临床研究，不仅用于血液恶性肿瘤，还用于实体瘤治疗。肿瘤。然而，由于 UPS 崩溃导致有毒的错误折叠蛋白质积累，蛋白酶体作为治疗因 UPS 损伤而持续的神经退行性疾病的靶标引起了更多的兴趣。因此，从概念上讲，蛋白酶体激活代表了药物开发的一个创新且很大程度上未经探索的目标。本综述将根据化学、生物化学、分子生物学和药理学的多学科方法，总结有关蛋白酶体生物学不同方面的最新文献，重点关注蛋白酶体在生理和病理过程（主要是癌症）中的结构、功能和调节。和神经退行性疾病，连接蛋白酶体靶向药物的生化特征和临床研究。