Li Lin, Liu Nana, Yang Pujuan, Rao Chunyan, Kong Lingna, Huang Yi, Lei Qingsong, Liu Huabao
Department of Hepatic Diseases, Chongqing Hospital of Traditional Chinese Medicine, 6 Seventh Branch of Panxi Road, Jiangbei, Chongqing, 400021, China.
School of Nursing, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Sci Rep. 2025 May 5;15(1):15659. doi: 10.1038/s41598-025-00540-2.
Ubiquitin-specific peptidase 18 (USP18) is a specific interferon-stimulated gene 15 demodifying enzyme that plays an important role in apoptosis. In this study, we investigated the role of USP18 in apoptosis in hepatocellular carcinoma cells, especially its ability to regulate apoptosis through endoplasmic reticulum (ER) stress. We found that protein levels of Bcl-2-associated protein x and cytochrome c were down-regulated by USP18, which suppressed the classical mitochondrial-mediated apoptosis pathway. USP18 also inhibited apoptosis through the unfolded protein response (UPR) pathway by inhibiting the phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and the expression of CCAAT/enhance-binding protein homologous protein, which is a downstream marker molecule of ER stress. The UPR triggered by ER stress eventually led to the cleavage of downstream effecter proteases, including caspase-3, leading to apoptosis. Furthermore, USP18 combined with a PERK agonist regulated apoptosis through the PERK-eukaryotic initiation factor-2α-activating transcription factor 4 axis of the UPR. Our results show that USP18 participates in the regulation of hepatocellular carcinoma cell apoptosis through different pathways, especially the ER stress pathway, and that it plays a complex role in cell stress responses and apoptosis regulation.
泛素特异性蛋白酶18（USP18）是一种特异性的干扰素刺激基因15去修饰酶，在细胞凋亡中起重要作用。在本研究中，我们探究了USP18在肝癌细胞凋亡中的作用，尤其是其通过内质网（ER）应激调节细胞凋亡的能力。我们发现，USP18下调了Bcl-2相关蛋白x和细胞色素c的蛋白水平，从而抑制了经典的线粒体介导的凋亡途径。USP18还通过抑制蛋白激酶RNA样内质网激酶（PERK）的磷酸化以及CCAAT/增强子结合蛋白同源蛋白（一种ER应激的下游标记分子）的表达，通过未折叠蛋白反应（UPR）途径抑制细胞凋亡。ER应激引发的UPR最终导致包括半胱天冬酶-3在内的下游效应蛋白酶的裂解，从而导致细胞凋亡。此外，USP18与PERK激动剂结合，通过UPR的PERK-真核起始因子-2α-激活转录因子4轴调节细胞凋亡。我们的结果表明，USP18通过不同途径参与肝癌细胞凋亡的调节，尤其是ER应激途径，并且它在细胞应激反应和凋亡调节中发挥着复杂的作用。
