Engineering Iridium Nanoclusters for Boosting Ferroptotic Cell Death by Regulating GPX4 and p53 Functions

Abstract Emerging evidence indicates that modulating glutathione peroxidase 4 (GPX4) to induce ferroptosis is a promising strategy for tumor treatment. However, most of the GPX4 small molecule inhibitors face limitations due to their poor delivery efficacy and low specificity of ferroptosis activation. Herein, a ferroptosis‐inducing nanomedicine is developed that integrates nutlin‐3 with iridium oxide nanoclusters (NUT‐IrO x NCs) for enhanced ferroptosis‐driven multimodal therapeutic efficacy in colorectal cancer (CRC). This NUT‐IrO x NCs can induce glutathione (GSH) depletion via enhanced Ir (VI)‐Ir (III) transition, while nutlin‐3, a well‐established inhibitor of the p53‐MDM2 interaction, suppresses GSH production by modulation of the p53/SLC7A11/xCT signaling pathway. The reduction of intracellular GSH results in pronounced reductions of GPX4 enzymatic activity, consequently leading to lipid peroxidation accumulation and further enhancing ferroptosis‐induced CRC therapy. This dual‐pronged approach demonstrates robust anticancer therapeutic effects with favorable biocompatibility in both in vitro and in vivo CRC models. This study provides an effective strategy that highlights the benefits of inhibiting of GSH/GPX4 by activating multiple ferroptosis regulatory pathways, providing an alternative therapeutic avenue for CRC treatment.