A promising new approach to cancer therapy: Manipulate ferroptosis by hijacking endogenous iron

Ferroptosis, a form of regulated cell death characterized by iron-dependent phospholipid peroxidation, has emerged as a focal point in the field of cancer therapy. Compared with other cell death modes such as apoptosis and necrosis, ferroptosis exhibits many distinct characteristics in the molecular mechanisms and cell morphology, offering a promising avenue for combating cancers that are resistant to conventional therapeutic modalities. In light of the serious side effects associated with current Fenton-modulating ferroptosis therapies utilizing exogenous iron-based inorganic nanomaterials, hijacking endogenous iron could serve as an effective alternative strategy to trigger ferroptosis through targeting cellular iron regulatory mechanisms. A better understanding of the underlying iron regulatory mechanism in the process of ferroptosis has shed light on the current findings of endogenous ferroptosis-based nanomedicine strategies for cancer therapy. Here in this review article, we provide a comprehensive discussion on the regulatory network of iron metabolism and its pivotal role in ferroptosis, and present recent updates on the application of nanoparticles endowed with the ability to hijack endogenous iron for ferroptosis. We envision that the insights in the study may expedite the development and translation of endogenous ferroptosis-based nanomedicines for effective cancer treatment.