Ginsenoside RK3 suppresses osteosarcoma via PRMT5/GPX4-ferroptosis axis and enhances doxorubicin chemosensitivity.
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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.