Targeting ferroptosis induction via nanomaterials in hepatocellular carcinoma: an insight into mechanism and therapeutic potential

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, continues to be a leading cause of cancer-related deaths worldwide, despite the development of new treatment options, including systemic regimens, locoregional treatments, transplantation, and resection. Significant etiological and genetic heterogeneity, an immunosuppressive tumor microenvironment, dose-limiting toxicities, and high rates of post-treatment recurrence continue to inhibit robust responses. Given the crucial role of the liver in iron metabolism and oxidative homeostasis, ferroptosis-a controlled, iron-dependent cell death triggered by glutathione depletion, GPX4 inactivation, and lipid peroxidation, has become a potential therapeutic vulnerability in HCC. However, the risk of off-target oxidative damage, insufficient intratumoral transport, and the poor solubility and pharmacokinetics of small-molecule ferroptotic inducers limit the therapeutic application of ferroptosis induction.The current review is novel to the best of our knowledge, focusing on a targeted and current synthesis of nanomaterials delivering ferroptotic inducers in order to induce ferroptosis in HCC as a next-generation therapeutic paradigm. We describe how constructed nanoplatforms allow for spatiotemporally controlled ROS formation and iron-catalyzed lipid peroxidation, while also improving tumor-selective accumulation of ferroptosis triggers, extending circulation, and improving stability. In order to transform ferroptotic stress into antitumor immunity, we highlight ferroptotic inducing nanomaterials that co-deliver ferroptosis inducers alongwith chemotherapeutics or photothermal/photodynamic agents, and immunomodulatory designs that invoke innate immune pathways like cGAS-STING. This work establishes ferroptosis-inducing nanomedicine as a new and quickly developing field with the potential to overcome resistance, expand therapeutic windows, and enhance long-term outcomes for patients with HCC.