Ginsenoside Rk1 suppresses osteosarcoma progression by coordinately activating ferritinophagy and disrupting antioxidant defense to induce ferroptosis.
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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.