Nhung Dinh Thi, Yousif Obadah E A, Kwon Byungsuk
School of Biomedical Health Science and Engineering, Ulsan, 44610, Republic of Korea.
Graduate School of Biomedical Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.
Biochem Biophys Rep. 2025 Jul 7;43:102143. doi: 10.1016/j.bbrep.2025.102143. eCollection 2025 Sep.
Sorafenib, a multi-kinase inhibitor, has been shown to induce ferroptosis, a form of lipid peroxidation-mediated cell death. However, a mechanism of how sorafenib-induced ER stress leads to ferroptosis remains unclear. Here, we report that the CCAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is a critical mediator linking ER stress to ferroptosis in human renal cell carcinoma (RCC) cells after exposure to sorafenib. A large portion of sorafenib-induced cell death was shown to be caused by ferroptosis and ER stress significantly contributed to this ferroptic cell death. Among three major ER stress pathways, sorafenib specifically induced activation of the ATF4-CHOP axis. CHOP in turn functioned as an effector suppressing expression of SLC7A11. Therefore, our results suggest that sorafenib induces ferroptosis in RCC cells by increasing uncontrolled oxidative stress.
索拉非尼是一种多激酶抑制剂，已被证明可诱导铁死亡，这是一种脂质过氧化介导的细胞死亡形式。然而，索拉非尼诱导的内质网应激如何导致铁死亡的机制仍不清楚。在此，我们报告CCAAT/增强子结合蛋白（C/EBP）同源蛋白（CHOP）是索拉非尼处理后将人肾细胞癌（RCC）细胞中的内质网应激与铁死亡联系起来的关键介质。大部分索拉非尼诱导的细胞死亡被证明是由铁死亡引起的，内质网应激显著促成了这种铁死亡性细胞死亡。在三个主要的内质网应激途径中，索拉非尼特异性诱导激活ATF4-CHOP轴。CHOP反过来作为效应器抑制SLC7A11的表达。因此，我们的结果表明，索拉非尼通过增加不受控制的氧化应激在RCC细胞中诱导铁死亡。
