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Updated: Jun 30, 2026
A Syngeneic Orthotopic Osteosarcoma Sprague Dawley Rat Model with Amputation to Control Metastasis Rate
Published on: May 3, 2021
Ginsenoside Rk1 suppresses osteosarcoma progression by coordinately activating ferritinophagy and disrupting
Renjin Lin1, Jianlong Wu1, Renpeng Fang1
1Center for Plastic & Reconstructive Surgery, Department of Hand & Reconstructive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
Abstract:
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Despite advances in multimodal therapy, the prognosis of metastatic or recurrent OS remains poor due to chemoresistance and limited therapeutic options. In this study, we systematically investigated the antitumor efficacy and molecular mechanisms of ginsenoside Rk1 (GRk1), a rare saponin derived from Panax ginseng, in OS models. GRk1 markedly suppressed cell viability, clonogenic growth, migration, and epithelial-mesenchymal transition (EMT), while promoting tumor cell death in a dose- and time-dependent manner. Mechanistically, GRk1 disrupted cellular redox homeostasis by decreasing mitochondrial membrane potential and promoting ROS accumulation. Integrated transcriptomic and biochemical analyses demonstrated that GRk1 induced ferroptosis through coordinated regulation of iron metabolism and antioxidant defense pathways. GRk1 activated AMPK while suppressing mTOR signaling, leading to NCOA4-dependent ferritinophagy, ferritin degradation, and intracellular iron accumulation. Simultaneously, GRk1 inhibited Nrf2 nuclear translocation, thereby promoting autophagic degradation of SLC7A11 and suppressing the SLC7A11/GSH/GPX4 antioxidant axis, ultimately exacerbating lipid peroxidation. Pharmacological rescue experiments using dorsomorphin and TBHQ confirmed the involvement of the AMPK/mTOR/NCOA4 and Nrf2/SLC7A11/GPX4 pathways, respectively. Furthermore, GRk1 synergistically potentiated the cytotoxic effects of cisplatin. In a xenograft mouse model, GRk1 effectively inhibited tumor growth without inducing significant systemic toxicity. Collectively, these findings identify GRk1 as a potent natural ferroptosis inducer and support its potential development as a promising adjuvant therapeutic strategy for OS.
Insights
Ginsenoside Rk1 (GRk1) effectively combats osteosarcoma by inducing ferroptosis, a cell death pathway. This natural compound shows promise as an adjuvant therapy, enhancing chemotherapy and inhibiting tumor growth.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Osteosarcoma (OS) is a primary bone cancer in children with poor outcomes due to chemoresistance.
- Limited therapeutic options exist for metastatic or recurrent OS.
Purpose of the Study:
- To investigate the antitumor effects and molecular mechanisms of ginsenoside Rk1 (GRk1) in osteosarcoma models.
- To explore GRk1's potential as an adjuvant therapy for OS.
Main Methods:
- In vitro studies on OS cell lines assessing viability, migration, and cell death.
- Transcriptomic and biochemical analyses to elucidate molecular pathways.
- In vivo xenograft mouse model to evaluate therapeutic efficacy and toxicity.
- Pharmacological rescue experiments to confirm pathway involvement.
Main Results:
- GRk1 suppressed OS cell viability, migration, and epithelial-mesenchymal transition, inducing cell death.
- GRk1 triggered ferroptosis by disrupting redox homeostasis, activating AMPK/mTOR/NCOA4, and inhibiting the Nrf2/SLC7A11/GPX4 antioxidant axis.
- GRk1 demonstrated synergistic effects with cisplatin and inhibited tumor growth in vivo without significant toxicity.
Conclusions:
- Ginsenoside Rk1 is a potent natural inducer of ferroptosis in osteosarcoma.
- GRk1 exhibits significant antitumor efficacy and warrants further investigation as an adjuvant therapy for OS.
