Targeting ferroptosis with flavonoids for cancer therapy: Mechanisms and opportunities

Ferroptosis, an iron-dependent regulated cell death mechanism driven by lipid peroxidation, offers a novel therapeutic approach for cancer treatment. Flavonoids, a diverse group of polyphenolic compounds, demonstrate significant anticancer potential by modulating ferroptosis pathways, including iron metabolism, GPX4 inhibition, and lipid peroxidation. This study examines flavonoid-induced ferroptosis mechanisms and their therapeutic applications. A systematic review of preclinical and clinical studies evaluated flavonoid effects (quercetin, baicalein, luteolin) on ferroptosis in cancer models. Key mechanisms analyzed included iron pool modulation, GPX4/System Xc^- inhibition, and lipid peroxidation enhancement. Synergistic interactions with chemotherapy, immunotherapy, and radiotherapy were assessed. Flavonoids trigger ferroptosis by (1) elevating labile iron to form redox-active complexes that can disrupt homeostasis and amplify Fenton reactions, (2) suppressing GPX4 and System Xc^- leading to glutathione depletion and ROS elevation, and (3) upregulating ACSL4/LOX to intensify lipid peroxidation. Preclinical data confirm efficacy in resistant cancers (triple-negative breast cancer, glioblastoma, pancreatic adenocarcinoma) and synergy with standard therapies. Challenges like poor bioavailability and tumor heterogeneity highlight the need for advanced delivery systems (nanoparticles, prodrugs). Flavonoids are promising ferroptosis inducers for apoptosis-resistant cancers, leveraging multi-target mechanisms and emerging delivery technologies. Future research should prioritize clinical translation, biomarker identification, and optimized combination regimens to enhance therapeutic outcomes.