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

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

  • Phytomedicine. 2025 Jul:142:156773. doi: 10.1016/j.phymed.2025.156773.
Chengli Wen 1,  Xu Zhang 2,  Jiraporn Kantapan 3,  Zehui Yu 4,  Liping Yuan 5,  Sha Liu 6,  Hao Li 7,  Sicheng Liang 8,  Yan Wei 9,  Gang Luo 10,  Wanmeng Xiao 11,  Nathupakorn Dechsupa 12,  Muhan Lü 13
Affiliations

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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