Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 28, 2025; 31(32): 108654
Published online Aug 28, 2025. doi: 10.3748/wjg.v31.i32.108654
Melatonin-induced ferroptosis in pancreatic cancer cells by stimulating endoplasmic reticulum stress and inhibiting alanine-serine-cysteine transporter 2-driven glutamine metabolism
Qian Zhao, Hui Zhang, Huang-Min Wu, Qun-Ying Yang, Hong Zhao, Le Kang, Xiang-Yin Lv
Qian Zhao, Huang-Min Wu, Qun-Ying Yang, Hong Zhao, Xiang-Yin Lv, Department of Gastroenterology, Dongyang People’s Hospital, Dongyang 322100, Zhejiang Province, China
Hui Zhang, Department of Gastroenterology, Weishan Branch of Dongyang People’s Hospital, Dongyang 322100, Zhejiang Province, China
Le Kang, Department of Scientific Research, Dongyang People’s Hospital, Dongyang 322100, Zhejiang Province, China
Co-first authors: Qian Zhao and Hui Zhang.
Author contributions: Lv XY and Zhao Q conceptualized the study; Zhao Q and Zhang H contributed equally as co-first authors; Zhao Q and Wu HM conducted the experiments; Zhao Q and Yang QY handled data collection; Lv XY and Kang L carried out the data analysis; Zhao Q and Zhao H drafted the initial manuscript; Lv XY and Wu HM reviewed and refined the final version of the manuscript; all authors approved the final version of the article.
Supported by Jinhua Municipal Science and Technology Bureau, No. 2022-4-254.
Institutional review board statement: This study does not involve any animal or human experiment, therefore it does not require approval from an ethics committee.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The datasets and materials utilized in this research are available from the corresponding author upon request.
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: Xiang-Yin Lv, Professor, Department of Gastroenterology, Dongyang People’s Hospital, No. 60 Wuning West Road, Dongyang 322100, Zhejiang Province, China. lvxiangyin1982@163.com
Received: June 10, 2025
Revised: July 10, 2025
Accepted: August 4, 2025
Published online: August 28, 2025
Processing time: 77 Days and 16.6 Hours
Abstract
BACKGROUND

Pancreatic cancer, characterized by aggressive proliferation and metastasis, is a lethal malignancy. The nightly hormone melatonin serves as a rhythm-regulating hormone, and is used to treat different cancers including pancreatic cancer.

AIM

To investigate how melatonin acts against human pancreatic cancer cell lines and analyze the biological processes that cause the observed effects.

METHODS

Panc-1 and AsPC-1 cells were treated with melatonin. Cell viability was measured using the cell counting kit-8 assay. Western blotting and immunofluorescence were used to analyze protein expression levels. Ferroptosis was measured by analyzing lipid reactive oxygen species and malondialdehyde levels; apoptosis was assessed using flow cytometry.

RESULTS

Melatonin significantly inhibited the viability, colony formation, migration, and invasion of Panc-1 and AsPC-1 cells. Additionally, melatonin activated the endoplasmic reticulum (ER) stress pathway (protein kinase R-like ER kinase-eukaryotic initiation factor 2α-activating transcription factor 4), inhibited glutamine metabolism (alanine-serine-cysteine transporter 2-glutaminase 1-glutathione peroxidase 4, alanine-serine-cysteine transporter 2-glutathione peroxidase 4), and promoted ferroptosis in pancreatic cancer cells. Co-treatment with a high melatonin concentration and protein kinase R-like ER kinase agonist (CCT020312) enhanced melatonin-induced ferroptosis in pancreatic cancer cells. Melatonin demonstrated a variety of anticancer effects by inhibiting autophagy. This was achieved through the increased expression of sequestosome-1 and decreased expression of light chain 3. Additionally, melatonin facilitated the promotion of apoptosis.

CONCLUSION

Melatonin induces ferroptosis in pancreatic cancer cells by activating transcription factor 4-dependent ER stress and inhibiting glutamine metabolism, promotes apoptosis in pancreatic cancer cells, and inhibits autophagy, leading to synergistic anticancer effects.

Keywords: Melatonin; Pancreatic cancer; Activating transcription factor 4; Alanine-serine-cysteine transporter 2; Ferroptosis

Core Tip: In the present study, we demonstrate that melatonin activates endoplasmic reticulum stress-mediated-ferroptosis in the protein kinase R-like endoplasmic reticulum kinase-eukaryotic initiation factor 2α-activating transcription factor 4 axis via inhibition of the alanine-serine-cysteine transporter 2-glutathione peroxidase 4 signaling pathway, thereby exerting an anti-cancer effect on pancreatic cancer cells. These new findings suggest that melatonin may act as a potent anti-tumor agent and may have great potential as an adjuvant therapy in the future.