Ginsenoside RK3 suppresses osteosarcoma via PRMT5/GPX4-ferroptosis axis and enhances doxorubicin chemosensitivity
5 affiliations
- 1Department of Orthopedics, The First Affiliated Hospital of Dalian Medical University
- 2Department of Orthopedics, Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital)
- 3First Operating Room, Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital)
- 4Department of Orthopedics, Golmud People’s Hospital
- 5Department of Neurology, Central Hospital of Dalian University of Technology (Dalian Municipal Central Hospital)
Abstract
Background: Osteosarcoma (OS), the most common primary malignant bone tumor in children and adolescents, commonly develops chemoresistance to conventional apoptosis-dependent therapies (e.g., doxorubicin) in metastatic/recurrent settings, leading to poor prognosis. Ferroptosis—an iron-dependent cell death pathway driven by lipid peroxidation—offers a promising alternative, yet clinical translation of synthetic inducers is limited by poor druggability.
Purpose: This study systematically investigates the antitumor efficacy of ginsenoside RK3 in OS, explores its potential involvement in the PRMT5/GPX4-ferroptosis axis, and evaluates its potential as a doxorubicin chemosensitizer.
Methods: Antitumor effects of RK3 were assessed in MG63/U2OS cells and OS xenografts. Mechanisms were explored through bioinformatics, molecular docking, co-immunoprecipitation, and ubiquitination assays. The combinatorial effects with doxorubicin (DOX) were evaluated in vitro and in vivo .
Results: RK3 potently suppressed OS growth and metastasis in vitro and in vivo without significant systemic toxicity. Mechanistically, molecular docking predicted that RK3 binds to PRMT5, and RK3 treatment downregulated PRMT5 expression, which was associated with enhanced FBW7–GPX4 interaction, increased GPX4 ubiquitination and proteasomal degradation, thereby promoting iron-dependent lipid peroxidation and ferroptosis. In combination with doxorubicin, RK3 markedly enhanced chemosensitivity and tumor suppression compared to monotherapy.
Conclusion: Ginsenoside RK3 inhibits OS potentially through the PRMT5/GPX4 axis to promote ferroptosis and enhances the sensitivity of tumors to doxorubicin, demonstrating a favorable safety profile. These findings suggest the PRMT5/GPX4 axis as a potential therapeutic target and position RK3 as a promising candidate for chemoresistant OS.
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BibTeX
@article{xu2026ginsenoside,
title = {{Ginsenoside RK3 suppresses osteosarcoma via PRMT5/GPX4-ferroptosis axis and enhances doxorubicin chemosensitivity}},
author = {Zhendong Xu and Zhuang Du and Qingshan Niu and Xin Wang and Huilin Wang and Meiyan Zhang and Mozhen Liu},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1980493},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1980493/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Ginsenoside RK3 suppresses osteosarcoma via PRMT5/GPX4-ferroptosis axis and enhances doxorubicin chemosensitivity
AU - Zhendong Xu
AU - Zhuang Du
AU - Qingshan Niu
AU - Xin Wang
AU - Huilin Wang
AU - Meiyan Zhang
AU - Mozhen Liu
PY - 2026
DA - 2026/10/23
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1980493
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1980493/full
AB - Background: Osteosarcoma (OS), the most common primary malignant bone tumor in children and adolescents, commonly develops chemoresistance to conventional apoptosis-dependent therapies (e.g., doxorubicin) in metastatic/recurrent settings, leading to poor prognosis. Ferroptosis—an iron-dependent cell death pathway driven by lipid peroxidation—offers a promising alternative, yet clinical translation of synthetic inducers is limited by poor druggability. Purpose: This study systematically investigates the antitumor efficacy of ginsenoside RK3 in OS, explores its potential involvement in the PRMT5/GPX4-ferroptosis axis, and evaluates its potential as a doxorubicin chemosensitizer. Methods: Antitumor effects of RK3 were assessed in MG63/U2OS cells and OS xenografts. Mechanisms were explored through bioinformatics, molecular docking, co-immunoprecipitation, and ubiquitination assays. The combinatorial effects with doxorubicin (DOX) were evaluated in vitro and in vivo . Results: RK3 potently suppressed OS growth and metastasis in vitro and in vivo without significant systemic toxicity. Mechanistically, molecular docking predicted that RK3 binds to PRMT5, and RK3 treatment downregulated PRMT5 expression, which was associated with enhanced FBW7–GPX4 interaction, increased GPX4 ubiquitination and proteasomal degradation, thereby promoting iron-dependent lipid peroxidation and ferroptosis. In combination with doxorubicin, RK3 markedly enhanced chemosensitivity and tumor suppression compared to monotherapy. Conclusion: Ginsenoside RK3 inhibits OS potentially through the PRMT5/GPX4 axis to promote ferroptosis and enhances the sensitivity of tumors to doxorubicin, demonstrating a favorable safety profile. These findings suggest the PRMT5/GPX4 axis as a potential therapeutic target and position RK3 as a promising candidate for chemoresistant OS.
SN - 1663-9812
ER -