Research Progress on Natural Products and Synergistic Nanostrategies for Targeting Ferroptosis in Osteosarcoma

Emerging evidence suggests that ferroptosis, a unique iron-dependent form of regulated cell death driven by lipid peroxidation and morphologically distinct from apoptosis or necrosis, plays a vital role in the pathophysiological progression and therapy resistance of osteosarcoma (OS). Accumulating evidence supports ferroptosis induction as a critical therapeutic strategy for OS, and pharmacological activation of ferroptosis by natural products represents a promising target for combating this malignancy. In this review, the core mechanisms of ferroptosis (including dysregulated iron/lipid/amino acid metabolism and autophagy-mediated regulation) and their roles in OS pathogenesis and chemoresistance are systematically described. Finally, emerging findings in treating OS through pharmacological induction of ferroptosis by bioactive natural compounds (e.g., flavonoids, curcuminoids, and terpenoids), functional nanomaterials (e.g., targeted drugloaded nanoparticles and GSH-depleting agents), and engineered exosomes are comprehensively summarized. Collectively, available evidence-predominantly from cell-line and xenograft studies-suggests that ferroptosis induction by natural products and nano/exosome-enabled delivery platforms can suppress OS growth and sensitize tumors to standard chemotherapeutics in preclinical models, including selected drug-resistant settings. However, clinical translation will require rigorous PK/PD and biodistribution characterization, definition of a therapeutic index and off-tumor ferroptosis liabilities, validation in orthotopic/bone-microenvironment models, and biomarker-guided stratification to identify responsive OS subsets.