Iron homeostasis and ferroptosis: a converging axis in cancer therapy

Cancer comprises a diverse group of complex diseases driven by genetic and epigenetic alterations that disrupt cellular signaling, metabolism, and cell death mechanisms. Despite significant advances in therapy, challenges such as tumor heterogeneity, treatment resistance, and escape from regulated cell death continue to impede curative outcomes. Among the various modes of regulated cell death, ferroptosis, an iron-dependent mechanism characterized by excessive lipid peroxidation and oxidative stress, has emerged as a promising therapeutic avenue in oncology. Notably, ferroptosis is intricately linked to iron homeostasis, providing a vulnerability that can be exploited by ferroptosis-targeted strategies in cancer, where iron metabolism is often dysregulated. This review provides a coherent account of the molecular mechanisms governing iron regulation and highlights how its imbalance can trigger ferroptosis. Additionally, we detail the molecular mechanisms of ferroptosis and summarize key regulatory networks, including system x_c-, GPx4, and the FSP1/CoQ10/NAD(P)H axis. Further, the role of natural and synthetic ferroptosis inducers is critically discussed, especially their synergistic potential when combined with chemotherapy, radiotherapy, and immunotherapy. Furthermore, this review explores emerging evidence on the regulation of ferroptosis by non-coding RNAs, hormonal regulation of ferroptosis sensitivity, and nanoparticle-based ferroptosis therapeutic strategies. Finally, the clinical relevance of ferroptosis in cancer therapy is discussed. Overall, this review presents ferroptosis as a promising therapeutic avenue, offering new insights into its integration with existing cancer treatment strategies.