Natural Agents Modulating Ferroptosis in Cancer: Molecular Pathways and Therapeutic Perspectives

Ferroptosis, a controlled cell death influenced by iron-dependent lipid peroxidation, presents potential therapeutic targets for cancer treatment due to its unique molecular pathways and potential drug resistance. Natural compounds, such as polyphenols, flavonoids, terpenoids and alkaloids, can influence ferroptosis via important signalling pathways, such as Nrf2/Keap1, p53, and GPX4. These are promising for combinational therapy due to their ability to cause ferroptotic death in cancer cells, exhibit tumour-specific selectivity and reduce systemic toxicity. Furthermore, these compounds, when combined with traditional chemotherapy or radiation therapy, can enhance therapeutic efficacy and overcome resistance. Natural compounds targeting ferroptosis offer innovative cancer treatment, particularly for resistant malignancies, due to their ability to interact with signalling pathways and produce specific cytotoxic effects. This review explores natural compounds' molecular mechanisms controlling ferroptosis in cancer, their interactions with traditional chemotherapeutics, translational hurdles, and clinical application directions, potentially leading to novel nature-inspired anticancer treatments. Further research and clinical trials are needed to confirm the safety, bioavailability, and effectiveness of ferroptosis medicines, focusing on improved formulation and transport methods.