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

Area of Science:

• Biomedical Engineering
• Oncology
• Nanotechnology

Background:

• Modulating glutathione peroxidase 4 (GPX4) to induce ferroptosis shows promise for cancer treatment.
• Existing GPX4 inhibitors face challenges in delivery and specificity for ferroptosis activation.

Purpose of the Study:

• To develop a ferroptosis-inducing nanomedicine for enhanced colorectal cancer (CRC) therapy.
• To investigate the combined effect of nutlin-3 and iridium oxide nanoclusters (NUT-IrOx NCs) on ferroptosis in CRC.

Main Methods:

• Development of NUT-IrOx NCs integrating nutlin-3 with iridium oxide nanoclusters.
• Induction of glutathione (GSH) depletion via Ir (VI)-Ir (III) transition and p53/SLC7A11/xCT pathway modulation.
• Evaluation of ferroptosis induction, lipid peroxidation, and therapeutic efficacy in vitro and in vivo CRC models.

Main Results:

• NUT-IrOx NCs effectively depleted intracellular GSH and reduced GPX4 activity.
• The nanomedicine induced significant lipid peroxidation, leading to enhanced ferroptosis.
• Demonstrated robust anticancer therapeutic effects and favorable biocompatibility in CRC models.

Conclusions:

• Dual inhibition of GSH/GPX4 via multiple ferroptosis pathways offers an effective strategy for CRC treatment.
• NUT-IrOx NCs provide a promising nanomedicine approach for ferroptosis-driven cancer therapy.
• This study presents a novel therapeutic avenue for colorectal cancer treatment.