A multifunctional nanocatalytic ferroptosis amplifier based on glutathione scavenging and lipid peroxidation amplification for cancer therapy

Abstract

Ferroptosis is a form of cell death characterized by decreased glutathione peroxidase 4 (GPX4) activity and amplification of lipid peroxidation cascades, efficiently disrupting cellular redox homeostasis. Photothermal therapy effectively regulates System Xc⁻, leading to the downregulation of GPX4, which plays a crucial role in promoting ferroptosis. However, the cellular self-protection mechanism of thermotolerance subsequently becomes a negative factor. Sonodynamic therapy (SDT) accumulates singlet oxygen (¹O₂), which facilitates the maintenance of reactive oxygen species and effectively alleviates thermotolerance during thermal elevation, while creating conditions for lipid peroxidation. This study constructed a nanodrug IrO_x@HMME-HSA, in which the iridium oxide (IrO_x) component guides photothermal effects and regulates the System Xc⁻–glutathione (GSH)–GPX4 route, and hematoporphyrin monomethyl ether (HMME) enables SDT to generate ROS and lipid peroxides and eliminate heat resistance. This provides a novel strategy to address the self-hypoxic characteristics of tumor microenvironments, antioxidant defenses, and laser-responsive heat tolerance issues. In addition, it lays theoretical and experimental foundations for the application of iridium-based nano-drugs in cancer therapy enhanced by ferroptosis through amplified GSH depletion.