Natural products mediate ferroptosis and immune microenvironment-linked sensitization in osteosarcoma: from chemotherapy resistance to combined therapeutic transformation.

Osteosarcoma is a primary bone tumor in adolescents and young adults, characterized by high chemotherapy resistance and poor prognosis. Ferroptosis, an iron‑dependent and lipid-peroxidation‑driven cell death, has become a key target to overcome chemoresistance and inhibit tumor progression. Natural products, with structural diversity, multi‑target regulation, and low toxicity, show great potential in ferroptosis‑based osteosarcoma therapy. This review summarizes the core molecular mechanisms of ferroptosis, focusing on the regulatory networks of Xc⁻-GSH-GPX4, Nrf2/HMOX1, p53, MAPK, and STAT3 pathways in osteosarcoma. It further categorizes natural products (flavonoids, terpenoids, alkaloids, naphthoquinones, and isothiocyanates) and discusses their targets and mechanisms in inducing ferroptosis. Current bottlenecks, including insufficient mechanistic validation, poor target specificity, limited clinical translation, and a lack of combination therapy strategies, are critically assessed. Future research directions are also proposed. This review aims to provide a theoretical basis and new insights for developing natural-product-based ferroptosis‑targeting drugs to address clinical treatment dilemmas in osteosarcoma.