Esculetin triggers ferroptosis via inhibition of the Nrf2-xCT/GPx4 axis in hepatocellular carcinoma.
10.1016/S1875-5364(25)60853-3
- Author:
Zhixin QU
1
;
Jing ZENG
1
;
Laifeng ZENG
2
;
Xianmei LI
3
,
4
;
Fenghua ZHANG
5
Author Information
1. Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China.
2. Fujian Key Laboratory of Integrative Medicine on Geriatrics, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
3. Fujian Key Laboratory of Integrative Medicine on Geriatrics, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China. Electronic address: lixianmei33@
4. com.
5. Key Laboratory of Gastrointestinal Cancer (Ministry of Education), School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China. Electronic address: zfh0606@fjmu.edu.cn.
- Publication Type:Journal Article
- Keywords:
Esculetin;
Ferroptosis;
Hepatocellular carcinoma;
Nrf2-xCT/GPx4 axis;
Zebrafish
- MeSH:
Umbelliferones/administration & dosage*;
Ferroptosis/drug effects*;
Carcinoma, Hepatocellular/physiopathology*;
NF-E2-Related Factor 2/genetics*;
Humans;
Liver Neoplasms/physiopathology*;
Phospholipid Hydroperoxide Glutathione Peroxidase/genetics*;
Animals;
Cell Line, Tumor;
Mice;
Amino Acid Transport System y+/genetics*;
Mice, Inbred BALB C;
Male;
Signal Transduction/drug effects*;
Lipid Peroxidation/drug effects*;
Reactive Oxygen Species/metabolism*;
Mice, Nude
- From:
Chinese Journal of Natural Medicines (English Ed.)
2025;23(4):443-456
- CountryChina
- Language:English
-
Abstract:
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 Fe2+, 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.
