DPP4/NRF2/FSP1介导的非经典铁死亡通路在肝癌索拉非尼耐药过程中的作用机制研究

索拉非尼是临床治疗中晚期肝癌性价比最高的一线药物，其耐药性一直是影响疗效的枷锁。研究表明部分肝癌细胞对索拉非尼诱导的铁死亡极为敏感, 因此明确肝癌细胞的铁死亡抵抗机制有望为改善索拉非尼耐药提供新的策略。经典铁死亡过程是细胞发生铁依赖的脂质过氧化物堆积而引起的细胞死亡，是以GPX4介导的谷胱甘肽消耗的方式，而新近研究显示基于FSP1及甲羟戊酸途径的非经典铁死亡方式在肿瘤进程中也发挥重要作用，我们前期证实DPP4与脂质过氧化反应密切相关，抑制DPP4可提高肝癌对索拉非尼的敏感性，此外肝癌中DPP4表达与FSP1呈正相关，且分子层面可能通过NRF2调控FSP1的表达；因此我们推测肝癌中DPP4/NRF2/FSP1介导的铁死亡抵抗是索拉非尼耐药的重要因素之一。本课题拟在分子、细胞及模式动物水平探讨肝癌进程中DPP4/NRF2/FSP1介导非经典铁死亡通路在索拉非尼耐药过程中的作用机制。

Sorafenib is the most cost-effective first-line drug for the clinical treatment of advanced hepatocellular carcinoma. Its drug resistance has always been a yoke that affects efficacy. Ferroptosis is a recently discovered type of cell death that is different from the traditional sense of apoptosis, necrosis and autophagy. It is caused by iron-dependent glutamine consumption and lipid peroxide accumulation in cells. Studies have shown that some hepatocellular carcinoma cells are extremely sensitive to sorafenib-induced ferroptosis. Therefore, it is clear that the ferroptosis resistance mechanism of hepatocellular carcinoma cells is expected to provide new strategies for improving sorafenib sensitivity.The canonical process of ferroptosis is cell death caused by the accumulation of iron-dependent lipid peroxides in cells. It is a glutamine-dependent manner mediated by GPX4. However, recent studies have shown that non-canonical pathway of ferroptosis based on Ferroptosis Suppress Protein 1 (FSP1) and mevalonate pathway also plays an important role in the progress of tumor. We have previously confirmed that upregulation of DPP4 expression is one of the important causes of poor prognosis of hepatocellular carcinoma, and it is closely related to lipid peroxidation. The inhibition of DPP4 can increase the sensitivity of hepatocellular carcinoma to sorafenib. In addition, DPP4 expression in hepatocellular carcinoma is positively correlated with FSP1, and FSP1 expression may be regulated by NRF2 at the molecular level; therefore we speculate that DPP4/NRF2/FSP1-mediated non-canonical ferroptosis is one of the important reasons for sorafenib resistance. In order to confirm our hypothesis, this project intends to explore the mechanism of DPP4/NRF2/FSP1-mediated non-canonical ferroptosis pathway in the process of resistance to sorafenib in the progress of hepatocellular carcinoma at the level of the molecule, cell, Patient Derived Xenograft(PDX) model and various genetic background mouse strain, aiming at providing theoretical basis and scientific experimental data for the targeted DPP4/NRF2/FSP1 pathway combined with sorafenib in the treatment of advanced liver cancer through the development of this study.