文章：

Arvanil通过结合MICU1诱导肝细胞癌铁死亡

Arvanil induces ferroptosis of hepatocellular carcinoma by binding to MICU1 

原文发布日期：2023-11-20 

英文摘要：

Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate that requires research and improved treatment strategies. Chemotherapy is still one of the main methods of HCC treatment, but it may lead to drug resistance and damage to normal organs. Capsaicin, a naturally occurring active ingredient in chili peppers, has demonstrated anticancer properties in a variety of malignant tumor cell lines. However, the anti-cancer mechanism of capsaicin needs to be further explored in HCC. In this study, we utilized Arvanil, a non-stimulating synthetic capsaicin analog, in place of capsaicin. We found that Arvanil induced high mitochondrial calcium flow, which contributed to a decrease in mitochondrial membrane permeability transition pore (mPTP) opening and oxidative phosphorylation levels, ultimately triggering cellular ferroptosis by live cells in real time with a high content screening (HCS) platform and confocal microscopy. It was further confirmed by vina molecular docking and point mutation experiments that Arvanil directly binds to two amino acid sites of mitochondrial calcium uptake protein 1 (MICU1), namely Ser47 and Phe128, to trigger this process, which in turn inhibits the growth of HCC cells. In addition, it was confirmed that Arvanil enhances cisplatin chemosensitivity by inducing HCC cellular ferroptosis in vivo. In conclusion, our study suggests that Arvanil induces ferroptosis in HCC cells and is a candidate drug for the treatment of HCC. 

摘要翻译： 

肝细胞癌（HCC）是一种具有高死亡率的原发性肝癌，亟需深入研究并改进治疗策略。化疗仍是HCC主要治疗手段之一，但可能导致耐药性并对正常器官造成损伤。辣椒素是辣椒中天然存在的活性成分，已在多种恶性肿瘤细胞系中展现出抗癌特性，然而其对HCC的抗癌机制尚需进一步探索。本研究采用无刺激性的合成辣椒素类似物Arvanil替代辣椒素，通过高内涵筛选（HCS）平台和共聚焦显微镜实时观测发现，Arvanil诱导线粒体高钙流，导致线粒体膜通透性转换孔（mPTP）开放减少和氧化磷酸化水平降低，最终引发细胞铁死亡。分子对接和点突变实验进一步证实，Arvanil直接结合线粒体钙摄取蛋白1（MICU1）的Ser47与Phe128两个氨基酸位点触发该过程，进而抑制HCC细胞生长。此外，研究证实Arvanil通过诱导HCC细胞铁死亡增强体内顺铂化疗敏感性。综上，本研究表明Arvanil可诱导HCC细胞铁死亡，是一种潜在的治疗HCC候选药物。

原文链接：

Arvanil induces ferroptosis of hepatocellular carcinoma by binding to MICU1