Non-coding RNAs as master regulators of ferroptosis in cancer: mechanisms and clinical implications

Ferroptosis is a non-apoptotic form of cell death characterized by intracellular iron accumulation and the subsequent elevation of cytotoxic lipid peroxides. Various cellular metabolic pathways intricately regulate this process, including redox homeostasis, iron metabolism, lipid metabolism, and other signaling cascades. Increasing evidence substantiates the critical role of ferroptosis in tumorigenesis and cancer therapy. However, our current understanding of numerous mechanisms underlying tumor ferroptosis remains limited. Noncoding RNAs (ncRNAs) provide a new perspective. Several ncRNAs, particularly microRNAs, long noncoding RNAs, and circular RNAs, are being demonstrated to form a comprehensive regulatory network that exerts direct regulation over ferroptosis-related genes or enzymes while indirectly modulating regulatory factors associated with ferroptosis. Strikingly, ncRNAs also serve as crucial mediators orchestrating communication between cancer cells, stromal cells, and immune cells within the tumor microenvironment (TME). Given their substantial potential in tumors and the TME, ferroptosis-related RNAs emerge as promising targets for immunotherapy and overcoming drug resistance. The development of novel nanomedicines for delivering ncRNAs is crucial in advancing antitumor therapy. This review comprehensively elucidates the regulatory mechanisms of ferroptosis-associated ncRNAs across various cancers, sheds light on their functions within the TME, explores their clinical potential to overcome drug resistance, and highlights unresolved questions.