Ginsenoside Rg5 Targets PRDX1 to Disrupt Redox Homeostasis and Induce Mitochondria-Dependent Apoptosis in Human

Hai-Lun Ye1, Ya-Ni Wang1, Gang-Ao Li1

  • 1Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China.

PubMed

Insights

Ginsenoside Rg5 inhibits the antioxidant enzyme PRDX1, crucial for liver cancer cell survival. This PRDX1 inhibition triggers cancer cell death and enhances chemotherapy effectiveness, offering new therapeutic strategies for hepatocellular carcinoma.

Area of Science:

  • Oncology
  • Biochemistry
  • Molecular Biology

Background:

  • Hepatocellular carcinoma (HCC) is a major cause of cancer mortality with limited treatments.
  • Cancer cells, including HCC, rely on metabolic and redox adaptations for survival.
  • Peroxiredoxin 1 (PRDX1) is overexpressed in HCC, neutralizing reactive oxygen species (ROS) and promoting tumor cell survival and drug resistance.

Purpose of the Study:

  • To identify small molecules that inhibit PRDX1 in hepatocellular carcinoma.
  • To investigate the mechanism of action of ginsenoside Rg5 (Rg5) as a PRDX1 inhibitor.
  • To evaluate the therapeutic potential of Rg5, alone and in combination with doxorubicin, for HCC treatment.

Main Methods:

  • Utilized human hepatocellular carcinoma HepG2 cells as an in vitro model.
  • Performed structural and functional analyses to determine Rg5's binding site and inhibitory effect on PRDX1.
  • Assessed the impact of Rg5 on ROS levels, mitochondrial function, apoptosis, and cell viability.
  • Evaluated the synergistic effect of Rg5 with doxorubicin on HCC cells.

Main Results:

  • Identified ginsenoside Rg5 (Rg5) as a novel small-molecule inhibitor of PRDX1.
  • Demonstrated that Rg5 directly binds to Asn145 of PRDX1, suppressing its peroxidase activity.
  • Showed that Rg5-induced PRDX1 inhibition leads to ROS accumulation, mitochondrial dysfunction, apoptosis, and death of HepG2 cells.
  • Confirmed that Rg5 enhances the antitumor efficacy of doxorubicin and may overcome chemoresistance.

Conclusions:

  • PRDX1 is a druggable vulnerability in liver cancer.
  • Ginsenoside Rg5 effectively inhibits PRDX1, inducing hepatocellular carcinoma cell death.
  • Rg5 shows promise as a therapeutic agent for HCC, particularly in combination therapies.

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