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2000
Volume 25, Issue 8
  • ISSN: 1568-0096
  • E-ISSN: 1873-5576
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Abstract

Background

Macranthoside B (MB) is a saponin compound extracted from honeysuckle that has been reported to exhibit significant medicinal values, particularly anti-tumor activities. This study aimed to evaluate the anticancer efficacy of MB in treating adenocarcinoma of the esophagogastric junction (AEG) and elucidate its underlying mechanisms.

Methods

Three AEG cell lines and normal gastric epithelial cells were used to assess the anticancer activity of MB . A series of experiments, including RNA sequencing (RNA-seq) analysis, transmission electron microscopy (TEM), immunofluorescence, and western blot assay, were conducted to validate the molecular mechanisms by which MB may mediate these physiological changes. Finally, we used shRNA assays to silence the key gene driving these changes and examined the expression of molecules involved in the affected pathways.

Results

MB exhibited significant anti-AEG cell activity with IC values ranging from 9.5 to 12.7 μM. RNA-seq results indicated that MB treatment in AEG cells significantly altered mRNA levels of autophagy- and ferroptosis-related genes. Further experiments revealed that MB treatment led to the up-regulation of lipid reactive oxygen species (Lip-ROS), oxidative stress-related pathway genes, and LC3B-labeled autophagic vesicles in AEG cells. Moreover, MB mediated NCOA4-dependent ferritinophagy, disrupting iron homeostasis and causing subsequent ferroptosis. We further confirmed that the intrinsic connection between autophagy and ferroptosis was due to the inhibition of NRF2 by MB. The inhibition of NRF2 by MB triggered transcriptional repression of its downstream effector molecules HERC2 and VAMP8, thus stabilizing NCOA4.

Conclusion

This study demonstrated MB to inhibit AEG cell growth by regulating iron homeostasis and inducing ferroptosis through the inhibition of NRF2, providing a basis for the development of novel drugs for AEG treatment.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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/content/journals/ccdt/10.2174/0115680096370291250109103853
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Macranthoside B Suppresses the Growth of Adenocarcinoma of Esophagogastric Junction by Regulating Iron Homeostasis and Ferroptosis through NRF2 Inhibition
Curr. Cancer Drug Targets< 25, 1013 (2025); https://doi.org/10.2174/0115680096370291250109103853
/content/journals/ccdt/10.2174/0115680096370291250109103853
/content/journals/ccdt/10.2174/0115680096370291250109103853
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  • Article Type:     Research Article
Keyword(s): AEG; ferritinophagy; iron homeostasis; Macranthoside B; NCOA4; NRF2

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