Endoplasmic reticulum (ER) stress, prompted by the accumulation of misfolded or unfolded proteins, triggers the activation of the unfolded protein response (UPR) pathway to restore ER homeostasis. This stress response is implicated in the development of hepatocellular carcinoma (HCC). A biallelic mutation in SPRTN is currently the only known single-gene mutation implicated in the early onset of HCC. However, the exact mechanism linking SPRTN mutations to HCC remains unclear. In our study, we analyzed SPRTN and UPR in 21 human HCC tissue samples using RT-qPCR, immunoblot, and immunohistochemistry. We found alterations in the expression levels of SPRTN and UPR-related genes and proteins in HCC samples. The impact of SPRTN on the ER stress response was assessed in SPRTN-depleted HepG2 cells through RNA sequencing, pull-down assay, comet assay, and mitotic index calculation. We demonstrated that SPRTN interacts with the UPR sensor GRP78. Furthermore, we observed a decrease in SPRTN levels during ER stress, and increased sensitivity to ER stress in SPRTN-depleted cells. These findings suggest an essential role for SPRTN in the ER stress response and provide new insights into HCC pathogenesis. This newly discovered function of SPRTN could significantly enhance our understanding and treatment of HCC.

由错误折叠或未折叠蛋白的积累引起的内质网（ER）应激，触发未折叠蛋白反应（UPR）途径的激活以恢复内质网稳态。这种应激反应与肝细胞癌（HCC）的发展有关。SPRTN中的双等位基因突变是目前唯一已知与 HCC 早期发病有关的单基因突变。然而，SPRTN 突变与 HCC 之间的确切机制仍不清楚。在我们的研究中，我们使用 RT-qPCR、免疫印迹和免疫组织化学分析了 21 个人类 HCC 组织样本中的 SPRTN 和 UPR。我们发现 HCC 样本中 SPRTN 和 UPR 相关基因和蛋白质的表达水平发生变化。通过 RNA 测序、pull-down 测定、彗星测定和有丝分裂指数计算，在 SPRTN 耗尽的 HepG2 细胞中评估 SPRTN 对 ER 应激反应的影响。我们证明了 SPRTN 与 UPR 传感器 GRP78 相互作用。此外，我们观察到 ER 应激期间 SPRTN 水平下降，并且 SPRTN 耗尽的细胞对 ER 应激的敏感性增加。这些发现表明 SPRTN 在 ER 应激反应中发挥着重要作用，并为 HCC 发病机制提供了新的见解。SPRTN 的这一新发现功能可以显着增强我们对 HCC 的理解和治疗。