PUBLICATION
Esculetin triggers ferroptosis via inhibition of the Nrf2-xCT/GPx4 axis in hepatocellular carcinoma
- Authors
- Qu, Z., Zeng, J., Zeng, L., Li, X., Zhang, F.
- ID
- ZDB-PUB-250425-13
- Date
- 2025
- Source
- Chinese Journal of Natural Medicines 23: 443456443-456 (Journal)
- Registered Authors
- Keywords
- Esculetin, Ferroptosis, Hepatocellular carcinoma, Nrf2-xCT/GPx4 axis, Zebrafish
- MeSH Terms
-
- Reactive Oxygen Species/metabolism
- Humans
- Male
- NF-E2-Related Factor 2*/genetics
- NF-E2-Related Factor 2*/metabolism
- Mice, Nude
- Ferroptosis*/drug effects
- Phospholipid Hydroperoxide Glutathione Peroxidase*/genetics
- Phospholipid Hydroperoxide Glutathione Peroxidase*/metabolism
- Cell Line, Tumor
- Mice
- Carcinoma, Hepatocellular*/drug therapy
- Carcinoma, Hepatocellular*/genetics
- Carcinoma, Hepatocellular*/metabolism
- Carcinoma, Hepatocellular*/physiopathology
- Lipid Peroxidation/drug effects
- Signal Transduction/drug effects
- Mice, Inbred BALB C
- Amino Acid Transport System y+*/genetics
- Amino Acid Transport System y+*/metabolism
- Liver Neoplasms*/drug therapy
- Liver Neoplasms*/genetics
- Liver Neoplasms*/metabolism
- Liver Neoplasms*/physiopathology
- Animals
- Umbelliferones*/administration & dosage
- Umbelliferones*/pharmacology
- PubMed
- 40274347 Full text @ Chin. J. Nat. Med.
Citation
Qu, Z., Zeng, J., Zeng, L., Li, X., Zhang, F. (2025) Esculetin triggers ferroptosis via inhibition of the Nrf2-xCT/GPx4 axis in hepatocellular carcinoma. Chinese Journal of Natural Medicines. 23:443456443-456.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping