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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.
Abstract:
Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, with limited therapeutic options and poor clinical outcomes. Mounting evidence suggests that targeting cancer-specific metabolic and redox adaptations represents a promising therapeutic strategy. Peroxiredoxin 1 (PRDX1), a key antioxidant enzyme that is frequently overexpressed in HCC, enables tumor cells to neutralize excessive reactive oxygen species (ROS), thereby sustaining survival and conferring therapeutic resistance. In this study, using human hepatocellular carcinoma HepG2 cells as an in vitro model, we identify ginsenoside Rg5 (Rg5) as a previously unrecognized small-molecule inhibitor of PRDX1. Structural and functional analyses demonstrate that Rg5 directly binds to the Asn145 residue of PRDX1, effectively suppressing its peroxidase activity. Mechanistically, this inhibition disrupts ROS detoxification in HepG2 cells, leading to mitochondrial ROS accumulation, activation of the intrinsic apoptotic pathway, and consequent HepG2 cell death. Additionally, Rg5 not only suppresses HepG2 cell survival but also acts synergistically with doxorubicin, a first-line chemotherapeutic agent, to markedly enhance antitumor efficacy and potentially mitigate chemoresistance. Collectively, these findings suggest that PRDX1 inhibition may represent a broadly exploitable vulnerability in liver cancer and establish Rg5 as a promising candidate for developing targeted and combinatorial therapies against HCC.
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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