A chiral fluorescent Ir(iii) complex that targets the GPX4 and ErbB pathways to induce cellular ferroptosis

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Ferroptosis is a promising anticancer target, but developing selective inducers with low normal cell toxicity is challenging.
• Existing strategies often struggle with tumour targeting and off-target effects, limiting therapeutic potential.

Purpose of the Study:

• To design and characterize a novel iridium(III) complex, Ir1, with selective ferroptosis-inducing capabilities for cancer treatment.
• To investigate the dual mechanisms of action of Ir1, including inhibition of key ferroptosis regulators and signalling pathways.
• To evaluate the efficacy and safety profile of Ir1 in preclinical cancer models.

Main Methods:

• Synthesis and characterization of the iridium(III) complex Ir1 containing a chiral pyridine RAS-selective lethal ligand (Py-RSL).
• In vitro studies to assess the inhibition of glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) in HT-1080 cells.
• Fluorescence microscopy for real-time cellular tracking and assessment of cytotoxicity in normal cells.
• Label-free quantitative proteomic profiling to identify simultaneously inhibited signalling pathways, including the ErbB pathway.

Main Results:

• Ir1 effectively inhibits both GPX4 and FSP1, inducing ferroptosis in human fibrosarcoma (HT-1080) cells.
• Metal coordination in Ir1 provides fluorescent properties for cellular tracking and significantly reduces the off-target toxicity of the Py-RSL ligand.
• Proteomic analysis revealed that Ir1 simultaneously inhibits the ErbB signalling pathway, contributing to enhanced tumour suppression.
• Ir1 demonstrates dual mechanisms of action, inducing ferroptosis and inhibiting cancer-promoting signalling pathways.

Conclusions:

• The novel iridium(III) complex Ir1 is a potent ferroptosis inducer with selective tumour targeting and reduced cytotoxicity.
• Ir1 exhibits dual inhibitory mechanisms, targeting key ferroptosis regulators (GPX4, FSP1) and the ErbB signalling pathway.
• This study presents a highly selective and efficient strategy for developing new ferroptosis-inducing metallodrugs for cancer therapy.