Qu Zhixin, Zeng Jing, Zeng Laifeng, Li Xianmei, Zhang Fenghua
Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China.
Fujian Key Laboratory of Integrative Medicine on Geriatrics, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
Chin J Nat Med. 2025 Apr;23(4):443-456. doi: 10.1016/S1875-5364(25)60853-3.
Esculetin, a natural dihydroxy coumarin derived from the Chinese herbal medicine Cortex Fraxini, has demonstrated significant pharmacological activities, including anticancer properties. Ferroptosis, an iron-dependent form of regulated cell death, has garnered considerable attention due to its lethal effect on tumor cells. However, the exact role of ferroptosis in esculetin-mediated anti-hepatocellular carcinoma (HCC) effects remains poorly understood. This study investigated the impact of esculetin on HCC cells both in vitro and in vivo. The findings indicate that esculetin effectively inhibited the growth of HCC cells. Importantly, esculetin promoted the accumulation of intracellular Fe, leading to an increase in ROS production through the Fenton reaction. This event subsequently induced lipid peroxidation (LPO) and triggered ferroptosis within the HCC cells. The occurrence of ferroptosis was confirmed by the elevation of malondialdehyde (MDA) levels, the depletion of glutathione peroxidase (GSH-Px) activity, and the disruption of mitochondrial morphology. Notably, the inhibitor of ferroptosis, ferrostatin-1 (Fer-1), attenuated the anti-tumor effect of esculetin in HCC cells. Furthermore, the findings revealed that esculetin inhibited the Nrf2-xCT/GPx4 axis signaling in HCC cells. Overexpression of Nrf2 upregulated the expression of downstream SLC7A11 and GPX4, consequently alleviating esculetin-induced ferroptosis. In conclusion, this study suggests that esculetin exerts an anti-HCC effect by inhibiting the activity of the Nrf2-xCT/GPx4 axis, thereby triggering ferroptosis in HCC cells. These findings may contribute to the potential clinical use of esculetin as a candidate for HCC treatment.
秦皮乙素是一种从中药秦皮中提取的天然二羟基香豆素，已显示出显著的药理活性，包括抗癌特性。铁死亡是一种铁依赖性的程序性细胞死亡形式，因其对肿瘤细胞的致死作用而备受关注。然而，铁死亡在秦皮乙素介导的抗肝癌（HCC）效应中的确切作用仍知之甚少。本研究调查了秦皮乙素在体外和体内对肝癌细胞的影响。研究结果表明，秦皮乙素能有效抑制肝癌细胞的生长。重要的是，秦皮乙素促进细胞内铁的积累，通过芬顿反应导致活性氧生成增加。这一事件随后诱导脂质过氧化（LPO）并引发肝癌细胞内的铁死亡。丙二醛（MDA）水平升高、谷胱甘肽过氧化物酶（GSH-Px）活性降低以及线粒体形态破坏证实了铁死亡的发生。值得注意的是，铁死亡抑制剂铁抑素-1（Fer-1）减弱了秦皮乙素对肝癌细胞的抗肿瘤作用。此外，研究结果显示秦皮乙素抑制肝癌细胞中的Nrf2-xCT/GPx4轴信号传导。Nrf2的过表达上调了下游SLC7A11和GPX4的表达，从而减轻了秦皮乙素诱导的铁死亡。总之，本研究表明秦皮乙素通过抑制Nrf2-xCT/GPx4轴的活性发挥抗肝癌作用，从而引发肝癌细胞的铁死亡。这些发现可能有助于秦皮乙素作为肝癌治疗候选药物的潜在临床应用。
