Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui Province Key Laboratory of R&D of Chinese Medicine, Anhui University of Traditional Chinese Medicine, 103 Meishan Road, Shushan District, Hefei City, 230038, Anhui Province, China.
Office of the Director, Institute of Pharmacology and Toxicology, Anhui Academy of Medical Sciences, Anhui Medical College, Hefei City, 230061, Anhui Province, China.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Jul;397(7):4895-4909. doi: 10.1007/s00210-023-02916-5. Epub 2024 Jan 2.
Hepatocellular carcinoma (HCC) is the most prevalent type of primary liver cancer, accounting for the overwhelming majority of malignant liver tumors. Therefore, how to effectively prevent and cure HCC has become a research hotspot. Many studies have shown that arenobufagin can induce apoptosis, ferroptosis, and autophagy of tumor cells. An increasing number of studies have shown that autophagy is closely linked to ferroptosis. In this study, HepG2 cells and BALB/c nude mice were used as research objects to explore the effect and preliminary mechanism of hepatoma cell autophagy and ferroptosis induced by arenobufagin. We found that arenobufagin can significantly inhibit tumor growth in vivo, and interestingly, we found that arenobufagin inhibited ferroptosis-related proteins Nrf2 and COX-2 in a dose-dependent manner and decreased the levels of reduced glutathione (GSH) and superoxide dismutase (T-SOD) in tissues, while increased the level of reduced malondialdehyde (MDA). In addition, we found that arenobufagin increased the levels of COX-2 and MDA in cells, decreased the levels of Nrf2, GSH, and T-SOD, increased the levels of tissue reactive oxygen species (ROS) and lipid ROS in a dose-dependent manner, and promoted ferroptosis in HepG2 cells. HepG2 cells were preprotected by autophagy inhibitor chloroquine (CQ) and ferroptosis inhibitor deferoxamine (DFO), and then treated with arenobufagin. It was found that CQ partially reversed the changes of COX-2 and Nrf2 expression and lipid peroxidation induced by arenobufagin-induced autophagy and HepG2 cells. Interestingly, CQ partially reversed the inhibition of arenobufagin on cytoplasmic junction protein (Keap1) and heme oxygenase-1 (HO-1) in p62-Keap1-Nrf2 pathway. At the same time, we found that the effect of arenobufagin on oxidative stress of HepG2 cells overexpressed by Nrf2 was significantly less than that of the control group. To sum up, arenobufagin promotes autophagy-dependent ferroptosis of HepG2 cells by inducing autophagy and regulating p62-Keap1-Nrf2 pathway. It is suggested that arenobufagin can be used as a potential intervention therapy.
肝细胞癌（HCC）是最常见的原发性肝癌，占恶性肝肿瘤的绝大多数。因此，如何有效预防和治疗 HCC 已成为研究热点。许多研究表明，华蟾酥毒基可以诱导肿瘤细胞凋亡、铁死亡和自噬。越来越多的研究表明，自噬与铁死亡密切相关。本研究以 HepG2 细胞和 BALB/c 裸鼠为研究对象，探讨华蟾酥毒基诱导肝癌细胞自噬和铁死亡的作用及初步机制。我们发现华蟾酥毒基能显著抑制体内肿瘤生长，有趣的是，我们发现华蟾酥毒基呈剂量依赖性抑制铁死亡相关蛋白 Nrf2 和 COX-2，降低组织中还原型谷胱甘肽（GSH）和超氧化物歧化酶（T-SOD）水平，同时增加还原型丙二醛（MDA）水平。此外，我们发现华蟾酥毒基增加细胞内 COX-2 和 MDA 水平，降低 Nrf2、GSH 和 T-SOD 水平，呈剂量依赖性增加组织内活性氧（ROS）和脂质 ROS 水平，促进 HepG2 细胞铁死亡。用自噬抑制剂氯喹（CQ）和铁死亡抑制剂去铁胺（DFO）预先保护 HepG2 细胞，然后用华蟾酥毒基处理。结果发现，CQ 部分逆转了华蟾酥毒基诱导的自噬和 HepG2 细胞 COX-2 和 Nrf2 表达及脂质过氧化的变化。有趣的是，CQ 部分逆转了华蟾酥毒基对细胞质连接蛋白（Keap1）和血红素加氧酶-1（HO-1）在 p62-Keap1-Nrf2 通路中的抑制作用。同时，我们发现过表达 Nrf2 的 HepG2 细胞对华蟾酥毒基氧化应激的作用明显小于对照组。综上所述，华蟾酥毒基通过诱导自噬和调节 p62-Keap1-Nrf2 通路，促进 HepG2 细胞自噬依赖性铁死亡。提示华蟾酥毒基可作为一种潜在的干预治疗方法。
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