Phillyrin regulates the JAK2/STAT3 signaling pathway by inhibiting TOP2A expression to accelerate ferroptosis in hepatocellular carcinoma

Zhu,Ying; Huang,Fenghe; Liu,Xiyu; Hou,Yunlong; Huang,Yong

doi:10.3892/or.2025.8876

Phillyrin regulates the JAK2/STAT3 signaling pathway by inhibiting TOP2A expression to accelerate ferroptosis in hepatocellular carcinoma

Authors:
- Ying Zhu
- Fenghe Huang
- Xiyu Liu
- Yunlong Hou
- Yong Huang
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Affiliations: State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China, Hebei Yiling Medical Research Institute Co., LTDS, Shijiazhuang, Hebei 050000, P.R. China
Published online on: February 12, 2025 https://doi.org/10.3892/or.2025.8876
Article Number: 43
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Despite advancements and refinements in the therapeutic approaches for hepatic malignancies, liver cancer remains a prevalent and deadly form of cancer, with its grim outlook posing as a significant clinical challenge. Phillyrin (PHN) has been reported to have anticancer effects, but the anticancer mechanism in liver cancer is ominous. By searching the potential target of PHN in the online database and liver cancer disease database, it was found that there is only one overlap gene, and DNA topoisomerase II alpha (TOP2A) is abnormally expressed in liver cancer tissues. TOP2A overexpression and downregulated hepatocellular carcinoma cell lines were then constructed in vitro, and it was examined whether PHN treatment induced ferroptosis in hepatocellular carcinoma by regulating TOP2A's inhibition of Janus kinase 2/Signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway through phenotypic assay, western blot assay, reverse transcription‑quantitative PCR assay and electron microscopy. The results showed that PHN could inhibit the expression of TOP2A protein and JAK2/STAT3 signaling pathway in hepatoma cells. PHN could also downregulate glutathione peroxidase 4 by suppressing the expression of TOP2A protein. PHN impeded the activity of factor inhibiting hypoxia‑inducible factor 1 alpha, thereby augmenting the synthesis of iron‑dependent apoptosis‑related proteins including cytochrome c oxidase subunit II, long‑chain acyl‑CoA synthetase family member 4 and NADPH oxidase 1, thus facilitating an increase in Fe²⁺ concentration and accelerating oxidative harm within hepatocellular carcinoma cells, culminating in the induction of ferroptotic cell death in these liver malignancy cells.

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