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Updated: May 16, 2025
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Published on: March 15, 2024
Wu-Mei-Wan promotes ferroptosis in gallbladder cancer through STAT3 negative regulation: An integrated HPLC,
Jingwei Zhao1, Liuqing Shi1, Yue Yang1
1Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; Research Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
Ethnopharmacological Relevance:
As a traditional Chinese medicine, Wu-Mei-Wan (WMW) has shown promise as a second-line treatment for gallbladder cancer, but its mechanism remains to be explored.
Aim Of The Study:
To determine the specific mechanism of WMW active ingredients (Palmatine et al.) inducing ferroptosis in gallbladder cancer (GBC) and its synergistic potential with gemcitabine.
Materials And Methods:
Subcutaneous tumor in nude mice was used to analyze the combined effect of gemcitabine. The effective components into blood were identified by HPLC. Combined with proteomics, network pharmacology and bioinformatics analysis, the effective components and targets of WMW promoting ferroptosis in GBC were identified in vitro and in vivo. The anticancer effects of WMW on different GBC cell lines were evaluated by CCK-8 assay, colony formation and EdU staining. A variety of molecular biology experiments were used to explore the mechanism.
Results:
WMW treatment enhanced the sensitivity of GBC to gemcitabine, which induced ferroptosis and effectively inhibited the malignant phenotype of GBC. Network pharmacology and blood component identification identified the key components of WMW inhibiting GBC. Palmitine and other components were identified as active components into the blood. Proteomics and molecular docking validation further revealed the STAT3-centered regulatory network in GBC cells. Molecular experiments have shown that WMW induced ferroptosis by negatively regulating downstream molecules of p-STAT3 transcription of GPX4, ACSL4, HIF1α, and FTH1.
Conclusions:
WMW induces ferroptosis in GBC through the p-STAT3 axis and enhances sensitivity to gemcitabine, suggesting the potential of WMW as a second-line therapeutic for GBC.
Insights
Wu-Mei-Wan (WMW) enhances gemcitabine
Area of Science:
- Oncology
- Pharmacology
- Traditional Chinese Medicine
Background:
- Gallbladder cancer (GBC) lacks effective second-line treatments.
- Wu-Mei-Wan (WMW), a traditional Chinese medicine, shows therapeutic potential for GBC.
- The precise mechanism of WMW in GBC requires elucidation.
Purpose of the Study:
- To investigate the ferroptosis-inducing mechanism of WMW active components in GBC.
- To evaluate the synergistic effects of WMW with gemcitabine in GBC treatment.
- To identify key WMW components and their targets in GBC.
Main Methods:
- In vivo and in vitro studies using GBC cell lines and mouse models.
- High-performance liquid chromatography (HPLC) for component identification.
- Proteomics, network pharmacology, bioinformatics, and molecular biology techniques.
Main Results:
- WMW enhanced GBC sensitivity to gemcitabine, inducing ferroptosis and inhibiting tumor growth.
- Palmatine identified as a key active component of WMW.
- WMW induced ferroptosis by downregulating p-STAT3 signaling pathway components (GPX4, ACSL4, HIF1α, FTH1).
Conclusions:
- WMW induces ferroptosis in GBC via the p-STAT3 pathway.
- WMW potentiates gemcitabine efficacy, suggesting its role as a second-line GBC therapy.
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