Journal of ethnopharmacology · 2025
Wu-Mei-Wan promotes ferroptosis in gallbladder cancer through STAT3 negative regulation: An integrated HPLC, proteomics, network pharmacology, and experimental validation study.
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Zhao Jingwei, Shi Liuqing, Yang Yue, Zhu Jiayun, Zhou Zhe, Dong Ping, Liu Shilei, Yang Ziyi, Gong Wei
Аннотация
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.
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.