Issue 5, 2023

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

Abstract

Ferroptosis has recently emerged as a non-apoptotic form of programmed cell death and promising target for anticancer treatment. However, it is challenging to discover ferroptosis inducers with both highly selective tumour targeting and low cytotoxicity to normal cells. Here, we report an Ir(III) complex, Ir1, that contains a novel chiral pyridine RAS-selective lethal ligand (Py-RSL). This complex effectively inhibits glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) to induce ferroptosis in human fibrosarcoma (HT-1080) cells. Notably, metal coordination not only endows Ir1 with fluorescent properties for convenient cellular real-time tracking but also efficiently reduces the off-target toxicity of the Py-RSL ligand. Furthermore, label-free quantitative proteomic profiling revealed that Ir1 simultaneously inhibits the ErbB signalling pathway to enhance tumour suppression. Our work is the first to report a ferroptosis-inducing iridium complex with dual mechanisms of inhibition and provides a highly selective and efficient route to develop new ferroptosis-inducing metallodrugs.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
09 nov 2022
Accepted
05 dec 2022
First published
09 jan 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2023,14, 1114-1122

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

X. Zhao, J. Zhang, W. Zhang, Z. Guo, W. Wei, X. Wang and J. Zhao, Chem. Sci., 2023, 14, 1114 DOI: 10.1039/D2SC06171F

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