综合应激反应（ISR）响应内在和外在刺激而被激活，在肿瘤进展和耐药性中发挥作用。然而，ISR 在肝癌中的调节作用和机制在很大程度上仍未被探索。在此，我们证明含 OTU 结构域的蛋白 3 (OTUD3) 是真核起始因子 2α (eIF2α) 的去泛素化酶，可拮抗 ISR 并抑制肝癌。 OTUD3 通过消除 eIF2α 上 K27 连接的多泛素化来减少 eIF2α 和激酶 EIF2AK3 之间的相互作用。小鼠中 OTUD3 缺陷会导致 ISR 增强并加速 N-亚硝基二乙胺诱导的肝细胞癌的进展。此外，与 eIF2α 磷酸化升高相关的 OTUD3 表达降低与人类肝癌的进展相关。此外，OTUD3表达减少导致的ISR激活使肝癌细胞对索拉非尼产生耐药性，而联合使用ISR抑制剂ISRIB可显着提高肝癌细胞对索拉非尼的敏感性。总的来说，这些发现阐明了肝癌中 ISR 的调节机制，并提供了对抗索拉非尼耐药性的潜在策略。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

The integrated stress response (ISR) is activated in response to intrinsic and extrinsic stimuli, playing a role in tumor progression and drug resistance. The regulatory role and mechanism of ISR in liver cancer, however, remain largely unexplored. Here, we demonstrate that OTU domain-containing protein 3 (OTUD3) is a deubiquitylase of eukaryotic initiation factor 2α (eIF2α), antagonizing ISR and suppressing liver cancer. OTUD3 decreases interactions between eIF2α and the kinase EIF2ΑK3 by removing K27-linked polyubiquitylation on eIF2α. OTUD3 deficiency in mice leads to enhanced ISR and accelerated progression of N-nitrosodiethylamine-induced hepatocellular carcinoma. Additionally, decreased OTUD3 expression associated with elevated eIF2α phosphorylation correlates with the progression of human liver cancer. Moreover, ISR activation due to decreased OTUD3 expression renders liver cancer cells resistant to sorafenib, while the combined use of the ISR inhibitor ISRIB significantly improves their sensitivity to sorafenib. Collectively, these findings illuminate the regulatory mechanism of ISR in liver cancer and provide a potential strategy to counteract sorafenib resistance.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.