Basic Study
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World J Gastrointest Oncol. Mar 15, 2025; 17(3): 98844
Published online Mar 15, 2025. doi: 10.4251/wjgo.v17.i3.98844
Chlorogenic acid induces hepatocellular carcinoma cell ferroptosis via PTGS2/AKR1C3/GPX4 axis-mediated reprogramming of arachidonic acid metabolism
Ling Wu, Hong-Yao Chen, Jing-Ting Zhang, Ren-Yi Yang, Zhi-Bin Wang, Pei-Sen Xue, Wei Peng, Ke-Xiong Li, Wen-Hui Gao, Pu-Hua Zeng
Ling Wu, Hong-Yao Chen, Jing-Ting Zhang, Ren-Yi Yang, Zhi-Bin Wang, Pei-Sen Xue, Wen-Hui Gao, College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
Wei Peng, Ke-Xiong Li, Department of Oncology, Hunan Provincial Hospital of Integrated Traditional Chinese and Western Chinese, Changsha 410006, Hunan Province, China
Pu-Hua Zeng, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Provincial Hospital of Integrated Traditional Chinese and Western Chinese, Changsha 410006, Hunan Province, China
Co-first authors: Ling Wu and Hong-Yao Chen.
Co-corresponding authors: Wen-Hui Gao and Pu-Hua Zeng.
Author contributions: Chen HY and Wu L designed the study, analyzed the data, and drafted the manuscript, and they contributed equally as co-first authors; Zhang JT completed all the revisions; Wu L performed the experiments; Zhang JT, Yang RY, Wang ZB, Xue PS, and Peng W collected and managed the data; Li KX, Gao WH, and Zeng PH designed and supervised the experiments; Gao WH and Zeng PH contributed equally as co-corresponding authors; all authors drafted the manuscript and ensured its integrity and accuracy of the work.
Supported by the National Natural Science Foundation of China, No. 82074425; Natural Foundation of Hunan Province, No. 2023JJ30364 and No. 2023JJ30361; Hunan Provincial Key R&D Program, No. 2023SK2057; Key Project of Hunan Provincial Administration of Traditional Chinese Medicine, No. A2023042.
Institutional review board statement: The research content of this manuscript does not involve human participants, so institutional review board approval was not required.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: All data generated or analyzed during this study are included in this published article and its supplementary information files. The original data will be available upon reasonable request to the corresponding authors.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Pu-Hua Zeng, MD, PhD, Professor, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine, No. 58 Lushan Road, Yuelu District, Changsha 410006, Hunan Province, China. zph120@126.com
Received: July 7, 2024
Revised: November 8, 2024
Accepted: December 16, 2024
Published online: March 15, 2025
Processing time: 221 Days and 20.7 Hours
Abstract
BACKGROUND

Ferroptosis is an iron-dependent programmed non-apoptotic cell death characterized by the accumulation of free iron ions and lipid peroxidation. It is associated with the inactivation of glutathione peroxidase (GPX) and the accumulation of lipid peroxides within cells. Ferroptosis is closely related to the occurrence and development of hepatocellular carcinoma (HCC). Chlorogenic acid (CGA), an important bioactive component found in 61 traditional Chinese medicines such as Eucommia ulmoides, has been extensively studied for its effects on various malignant tumors. However, the specific role and potential mechanism of CGA in HCC remain unclear.

AIM

To elucidate the anti-tumor characteristics and potential mechanisms of CGA in inducing ferroptosis in HCC cells.

METHODS

The effects of CGA on the proliferation, migration, and invasion of HCC cells were evaluated through in vitro experiments. Bioinformatics analysis combined with network pharmacology was used to study the potential targets and molecular mechanisms of CGA intervention in HCC ferroptosis. In vitro experiments were conducted to verify and explore the anti-HCC effects and mechanisms of CGA through the ferroptosis pathway.

RESULTS

In vitro experiments showed that CGA dose-dependently inhibited the proliferation, invasion, and migration of HCC cells. Bioinformatics analysis combined with network pharmacology revealed that the pathway of CGA intervention in HCC cell ferroptosis was mainly enriched in the prostaglandin endoperoxide synthase 2 (PTGS2)/aldo-keto reductase family 1 member C3 (AKR1C3)/GPX4 signaling pathway, which was associated with arachidonic acid. In vitro experiments further confirmed that CGA-induced ferroptosis in HCC cells was related to mitochondrial damage through the reprogramming of arachidonic acid metabolism by regulating the PTGS2/AKR1C3/GPX4 signaling pathway.

CONCLUSION

This study demonstrates that CGA inhibits HCC cell proliferation, migration, and invasion by inducing ferroptosis through the PTGS2/AKR1C3/GPX4 axis, suggesting its potential as a novel ferroptosis inducer or anti-HCC drug.

Keywords: Chlorogenic acid; Hepatocellular carcinoma; Ferroptosis; Prostaglandin endoperoxide synthase 2/aldo-keto reductase family 1 member C3/glutathione peroxidase 4 axis; Bioinformatics; In vitro experiment

Core Tip: This study reveals that chlorogenic acid (CGA) dose-dependently inhibits the proliferation, invasion, and migration of hepatocellular carcinoma (HCC) cells. Through bioinformatics analysis and network pharmacology, it is found that CGA induces ferroptosis in HCC cells by regulating the prostaglandin endoperoxide synthase 2/aldo-keto reductase family 1 member C3/glutathione peroxidase 4 signaling pathway, reprogramming arachidonic acid metabolism, and causing mitochondrial damage. This research highlights the potential of CGA as a novel ferroptosis inducer or anti-HCC therapeutic.