Pentagalloyl glucose targets the JAK1/JAK3-STAT3 pathway to inhibit cancer stem cells and epithelial-mesenchymal transition in 5-fluorouracil-resistant colorectal cancer

Chengli Wen¹, Xu Zhang², Jiraporn Kantapan³, Zehui Yu⁴, Liping Yuan⁵, Sha Liu⁶, Hao Li⁷, Sicheng Liang⁸, Yan Wei⁹, Gang Luo¹⁰, Wanmeng Xiao¹¹, Nathupakorn Dechsupa¹², Muhan Lü¹³

Affiliations

¹ Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Critical Care Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China. Electronic address: wenchengli076@swmu.edu.cn.
² Department of Gastroenterology, Honghuagang District People's Hospital of Zunyi City, Zunyi 563000, China. Electronic address: zhangxu290823@163.com.
³ Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand. Electronic address: jiraporn.kan@cmu.ac.th.
⁴ Laboratory Animal Center, Southwest Medical University, Luzhou 646000, China; Human Microecology and Precision Diagnosis and Treatment of Luzhou Key Laboratory, Luzhou 646000, China. Electronic address: yuzehui_swmu@outlook.com.
⁵ Department of Gastroenterology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China; Department of Gastroenterology, The First People's Hospital of Liangshan Yi Autonomous Prefecture, Xichang 615000, China. Electronic address: 475482551@qq.com.
⁶ Human Microecology and Precision Diagnosis and Treatment of Luzhou Key Laboratory, Luzhou 646000, China; The Clinical Medicine Research Center, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China. Electronic address: 643363075@qq.com.
⁷ Human Microecology and Precision Diagnosis and Treatment of Luzhou Key Laboratory, Luzhou 646000, China; Department of Gastroenterology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China. Electronic address: lihao128@swmu.edu.cn.
⁸ Human Microecology and Precision Diagnosis and Treatment of Luzhou Key Laboratory, Luzhou 646000, China; Department of Gastroenterology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China. Electronic address: liangpharm@swum.edu.cn.
⁹ Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China. Electronic address: weiyan.1111@swmu.edu.cn.
¹⁰ Department of Gastroenterology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China. Electronic address: gangluo820@126.com.
¹¹ Human Microecology and Precision Diagnosis and Treatment of Luzhou Key Laboratory, Luzhou 646000, China; Department of Gastroenterology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China; The Clinical Medicine Research Center, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China. Electronic address: hello_xwm@hotmail.com.
¹² Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand. Electronic address: nathupakorn.d@cmu.ac.th.
¹³ Human Microecology and Precision Diagnosis and Treatment of Luzhou Key Laboratory, Luzhou 646000, China; Department of Gastroenterology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China. Electronic address: lvmuhan@swmu.edu.cn.

PMID: 40378534
DOI: 10.1016/j.phymed.2025.156773

Free article

Pentagalloyl glucose targets the JAK1/JAK3-STAT3 pathway to inhibit cancer stem cells and epithelial-mesenchymal transition in 5-fluorouracil-resistant colorectal cancer

Chengli Wen et al. Phytomedicine. 2025 Jul.

Free article

. 2025 Jul:142:156773.

doi: 10.1016/j.phymed.2025.156773. Epub 2025 Apr 16.

Authors

Affiliations

¹ Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Critical Care Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China. Electronic address: wenchengli076@swmu.edu.cn.
² Department of Gastroenterology, Honghuagang District People's Hospital of Zunyi City, Zunyi 563000, China. Electronic address: zhangxu290823@163.com.
³ Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand. Electronic address: jiraporn.kan@cmu.ac.th.
⁴ Laboratory Animal Center, Southwest Medical University, Luzhou 646000, China; Human Microecology and Precision Diagnosis and Treatment of Luzhou Key Laboratory, Luzhou 646000, China. Electronic address: yuzehui_swmu@outlook.com.
⁵ Department of Gastroenterology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China; Department of Gastroenterology, The First People's Hospital of Liangshan Yi Autonomous Prefecture, Xichang 615000, China. Electronic address: 475482551@qq.com.
⁶ Human Microecology and Precision Diagnosis and Treatment of Luzhou Key Laboratory, Luzhou 646000, China; The Clinical Medicine Research Center, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China. Electronic address: 643363075@qq.com.
⁷ Human Microecology and Precision Diagnosis and Treatment of Luzhou Key Laboratory, Luzhou 646000, China; Department of Gastroenterology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China. Electronic address: lihao128@swmu.edu.cn.
⁸ Human Microecology and Precision Diagnosis and Treatment of Luzhou Key Laboratory, Luzhou 646000, China; Department of Gastroenterology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China. Electronic address: liangpharm@swum.edu.cn.
⁹ Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China. Electronic address: weiyan.1111@swmu.edu.cn.
¹⁰ Department of Gastroenterology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China. Electronic address: gangluo820@126.com.
¹¹ Human Microecology and Precision Diagnosis and Treatment of Luzhou Key Laboratory, Luzhou 646000, China; Department of Gastroenterology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China; The Clinical Medicine Research Center, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China. Electronic address: hello_xwm@hotmail.com.
¹² Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand. Electronic address: nathupakorn.d@cmu.ac.th.
¹³ Human Microecology and Precision Diagnosis and Treatment of Luzhou Key Laboratory, Luzhou 646000, China; Department of Gastroenterology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China. Electronic address: lvmuhan@swmu.edu.cn.

PMID: 40378534
DOI: 10.1016/j.phymed.2025.156773

Abstract

Background: Colorectal cancer (CRC) resistance to 5-fluorouracil (5-FU), primarily driven by cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT), remains a major clinical challenge, necessitating novel therapeutic strategies.

Purpose: This study aims to evaluate the therapeutic potential of pentagalloyl glucose (PGG), a bioactive compound derived from Bouea macrophylla seeds, in overcoming 5-FU resistance in CRC.

Method: Anti-tumor effects of PGG were investigated using two- and three-dimensional (2D and 3D) cell culture models and subcutaneous xenograft and metastatic mouse models. Transcriptome sequencing, western blotting, and pharmacological inhibitors were employed to elucidate the underlying molecular mechanisms.

Results: PGG demonstrated potent anti-CSC activity; suppressed EMT-driven invasion and metastasis; and induced apoptosis in 2D monolayers, 3D spheroid models, and xenograft tumor models. Mechanistically, PGG selectively inhibited the JAK1/JAK3-STAT3 signaling pathway, considerably reducing STAT3 phosphorylation. This disruption downregulated the expression of CSC markers (CD133 and CD44), EMT regulators (N-cadherin and vimentin), and anti-apoptotic proteins (Bcl-2), effectively sensitizing 5-FU-resistant CRC to therapy.

Conclusion: PGG inhibit dual-target of CSCs and EMT via JAK1/JAK3-STAT3 signaling pathway in 5-FU-resistant CRC, providing a novel therapeutic approach to overcome chemoresistance.

Keywords: 5-fluorouracil; Cancer stem cell; Colorectal cancer; Drug resistance; Epithelial‒mesenchymal transition; Pentagalloyl glucose.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no financial interests or personal relationships that could have influenced the work presented in this study. Moreover, they declare that there is no conflict of interest exist.

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Pentagalloyl glucose targets the JAK1/JAK3-STAT3 pathway to inhibit cancer stem cells and epithelial-mesenchymal transition in 5-fluorouracil-resistant colorectal cancer

Affiliations

Pentagalloyl glucose targets the JAK1/JAK3-STAT3 pathway to inhibit cancer stem cells and epithelial-mesenchymal transition in 5-fluorouracil-resistant colorectal cancer

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous