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Ginsenoside Rh3 induces pyroptosis and ferroptosis through the Stat3/p53/NRF2 axis in colorectal cancer cells

Authors :
Wu Yingchao
Pi Dajin
Zhou Shuyao
Yi Zhongjia
Dong Yangyang
Wang Wuhong
Ye Huan
Chen Yiliu
Zuo Qian
Ouyang Mingzi
Source :
Acta Biochimica et Biophysica Sinica, Vol 55, Pp 587-600 (2023)
Publication Year :
2023
Publisher :
China Science Publishing & Media Ltd., 2023.

Abstract

Ginsenoside Rh3 (GRh3) is a seminatural product obtained by chemical processing after isolation from Chinese herbal medicine that has strong antitumor activity against human tumors. However, its antitumor role remains to be elucidated. The aim of this study is to explore the mechanisms underlying the tumor suppressive activity of GRh3 from the perspective of pyroptosis and ferroptosis. GRh3 eliminates colorectal cancer (CRC) cells by activating gasdermin D (GSDMD)-dependent pyroptosis and suppressing solute carrier family 7 member 11 (SLC7A11), resulting in ferroptosis activation through the Stat3/p53/NRF2 axis. GRh3 suppresses nuclear factor erythroid 2-related factor 2 (NRF2) entry into the nucleus, leading to the decrease of heme oxygenase 1 (HO-1) expression, which in turn promotes NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and caspase-1 expression. Finally, caspase-1 activates GSDMD-dependent pyroptosis. Furthermore, GRh3 prevents NRF2 from entering the nucleus, which suppresses SLC7A11, causing the depletion of glutathione (GSH) and accumulation of iron, lipid reactive oxygen species (ROS) and malondialdehyde (MDA), and eventually leading to ferroptosis in CRC cells. In addition, GRh3 effectively inhibits the proliferation of CRC cells in vitro and in nude mouse models. Collectively, GRh3 triggers pyroptotic cell death and ferroptotic cell death in CRC cells via the Stat3/p53/NRF2 axis with minimal harm to normal cells, showing great anticancer potential.

Details

Language :
English
ISSN :
16729145
Volume :
55
Database :
Directory of Open Access Journals
Journal :
Acta Biochimica et Biophysica Sinica
Publication Type :
Academic Journal
Accession number :
edsdoj.13d4c90e45ad436794ec51eba7fa5878
Document Type :
article
Full Text :
https://doi.org/10.3724/abbs.2023068