泛素蛋白酶体途径 (UPP) 在自催化蛋白酶体复合物的帮助下调节蛋白质稳定性和正常细胞功能。研究将异常的蛋白酶体活性与恶性细胞联系起来，并发现蛋白酶体抑制剂作为各种类型癌症的治疗药物发挥着重要作用，特别是多发性骨髓瘤和套细胞淋巴瘤。硼替佐米是FDA批准的第一个用于治疗不同阶段多发性骨髓瘤的蛋白酶体抑制剂，通过抑制26S蛋白酶体、调节NF-κB、磷酸化Bcl-2、上调NOXA、阻断p53降解、激活caspase、产生反应活性来作用于癌细胞氧（ROS），并抑制血管生成。然而，由于周围神经病（PN）、血栓性微血管病（TMA）和急性间质性肾炎（AIN）等副作用，其疗效有限。因此，更好地了解其精确的作用机制可能有助于减轻这些副作用。在这篇综述中，我们讨论了硼替佐米的拟议作用机制和脱靶效应，以及下一代潜在蛋白酶体抑制剂药物在癌症治疗中的前景。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

The ubiquitin-proteasome pathway (UPP) regulates protein stability and normal cellular functions with the help of autocatalytic proteasome complex. Studies have linked aberrant proteasome activity to malignant cells and found that proteasome inhibitors play a significant role as therapeutic drugs for various types of cancer, specifically multiple myeloma and mantle cell lymphoma. Bortezomib, the first FDA-approved proteasome inhibitor for treating different stages of multiple myeloma, acts on cancer cells by inhibiting the 26S proteasome, modulating NF-κB, phosphorylating Bcl-2, upregulating of NOXA, blocking p53 degradation, activating caspase, generating reactive oxygen species (ROS), and inhibiting angiogenesis. However, its efficacy is limited due to side effects such as peripheral neuropathy (PN), thrombotic microangiopathy (TMA), and acute interstitial nephritis (AIN). Therefore, a better understanding of its precise mechanism of action may help mitigate these side effects. In this review, we have discussed the proposed mechanisms of action and off target effects of Bortezomib, along with the prospects of next generation potential proteasome inhibitor drugs in the treatment of cancer.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.