Natural products mediate ferroptosis and immune microenvironment-linked sensitization in osteosarcoma: from chemotherapy resistance to combined therapeutic transformation.
Dai Yuwen, Ding Wanjun
Abstract
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.
Key Findings
- Ferroptosis is a key target to overcome chemotherapy resistance and inhibit tumor progression in osteosarcoma.
- Natural products such as flavonoids, terpenoids, alkaloids, naphthoquinones, and isothiocyanates can induce ferroptosis through multiple regulatory pathways including Xc⁻-GSH-GPX4 and Nrf2/HMOX1.
- Current challenges include insufficient mechanistic validation, poor target specificity, limited clinical translation, and lack of combination therapy strategies.
Clinical Significance
Targeting ferroptosis with natural products offers a promising therapeutic strategy to overcome chemoresistance in osteosarcoma, potentially improving patient outcomes through novel combination therapies.
Citation
Dai Yuwen, Ding Wanjun. Natural products mediate ferroptosis and immune microenvironment-linked sensitization in osteosarcoma: from chemotherapy resistance to combined therapeutic transformation. Molecular diversity. 2026-Aug-28.