Ferroptosis and Oral Cancer: Leveraging Iron-Driven Cell Death for Innovative Therapeutic Strategies

Ferroptosis is a novel form of regulated cell death characterized by iron-dependent lipid peroxidation and distinct morphological changes. This process is driven by key mechanisms, including polyunsaturated fatty acid synthesis, lipid peroxidation, iron metabolism, and the glutathione peroxidase 4 antioxidant system. Owing to their altered redox balance and metabolic states, cancer cells are particularly susceptible to ferroptosis. Oncogenic signaling pathways such as those involving rat sarcoma viral oncogene homolog (RAS), nuclear factor erythroid 2–related factor 2 (NRF2), mechanistic target of rapamycin (mTOR), hypoxia, and tumor protein p53 (TP53) play critical roles in regulating ferroptosis sensitivity in cancer cells. Inducing ferroptosis has emerged as a promising therapeutic strategy to target therapy-resistant cancer cells, especially those exhibiting mesenchymal and dedifferentiated phenotypes. Various ferroptosis-inducing drugs, including sorafenib, cisplatin, and statins, have shown potential in cancer treatment. To enhance the efficacy and specificity of these agents, innovative drug delivery systems such as nanoparticles, hydrogels, and liposomes have been developed. These advanced delivery methods aim to improve drug stability, target specificity, and therapeutic outcomes. For instance, the suppression of ferroptosis could help prevent tumor initiation, minimize treatment-related side effects, and preserve immune cell function. This dual role of ferroptosis in cancer underscores the complexity of its interplay with cancer biology. Understanding the molecular mechanisms and context-dependent functions of ferroptosis is crucial for the development of effective therapeutic strategies. Targeting ferroptosis has marked potential for overcoming treatment resistance and improving therapeutic outcomes in oral cancer patients. A deeper understanding of the molecular pathways governing ferroptosis will enable the development of more precise and effective cancer treatments, ultimately enhancing patient outcomes.