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

Yingchao Wu; Dajin Pi; Shuyao Zhou; Zhongjia Yi; Yangyang Dong; Wuhong Wang; Huan Ye; Yiliu Chen; Qian Zuo; Mingzi Ouyang

doi:10.3724/abbs.2023068

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

Acta Biochim Biophys Sin (Shanghai). 2023 Apr 19;55(4):587-600. doi: 10.3724/abbs.2023068.

Authors

Yingchao Wu¹, Dajin Pi¹, Shuyao Zhou², Zhongjia Yi¹, Yangyang Dong³, Wuhong Wang¹, Huan Ye¹, Yiliu Chen¹, Qian Zuo⁴, Mingzi Ouyang¹

Affiliations

¹ School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China.
² College of Forestry and Landscape Architecture, South China Agricultural University, Guangzhou 510642, China.
³ Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China.
⁴ MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.

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.

Keywords: Stat3/p53/NRF2 axis; colorectal cancer; ferroptosis; ginsenoside Rh3; pyroptosis.

MeSH terms

Animals
Caspase 1
Colorectal Neoplasms* / drug therapy
Ferroptosis*
Glutathione
Humans
Mice
Mice, Nude
NF-E2-Related Factor 2 / genetics
Pyroptosis
STAT3 Transcription Factor
Tumor Suppressor Protein p53

Substances

ginsenoside Rh3
NF-E2-Related Factor 2
Tumor Suppressor Protein p53
Caspase 1
Glutathione
STAT3 protein, human
STAT3 Transcription Factor

Grants and funding

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 81873155 and 81403340), the Medical Scientific Research Foundation of Guangdong Province of China (No. A2018006) and the Project of Administration of Traditional Chinese Medicine of Guangdong Province of China (No. 20191079).