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Small-Molecule Ferritin Degrader as a Pyroptosis Inducer.

Yu Chen^1,2,3, Wen Li¹, Song Kwon¹

¹Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.

Journal of the American Chemical Society

|April 24, 2023

Summary

This summary is machine-generated.

Researchers developed a novel ferritin-targeting PROTAC (proteolysis targeting chimera) to induce iron overload stress in cancer cells, triggering pyroptosis and inhibiting tumor growth with minimal side effects.

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Area of Science:

Biochemistry
Oncology
Drug Development

Background:

Intracellular metabolic stress in malignant cells is crucial for understanding cancer pathology and developing therapies.
Targeting iron metabolism presents a promising avenue for anticancer strategies.

Purpose of the Study:

To develop ferritin-targeting proteolysis targeting chimeras (PROTACs) to induce iron excess stress in cancer cells.
To investigate the cellular response to induced iron overload and its therapeutic potential.

Main Methods:

Conjugation of oleic acid (binds to ferritin dimer) to a von Hippel-Lindau (VHL) E3 ligase ligand via an alkyl linker to create PROTACs.
Screening of the chimera DeFer-2 for its ability to degrade ferritin and elevate free iron.
Loading DeFer-2 into an albumin-based nano-formulation for in vivo studies.

Main Results:

The PROTAC DeFer-2 successfully degraded ferritin, leading to rapid intracellular free iron elevation.
This iron overload initiated caspase 3-GSDME-mediated pyroptosis in cancer cells, distinct from ferroptosis.
The nano-formulated DeFer-2 significantly inhibited tumor growth and prolonged survival in mice with B16F10 tumors, showing negligible adverse effects.

Conclusions:

A novel ferritin-targeting PROTAC was developed to induce iron overload stress.
Iron metabolic dysregulation was shown to mediate pyroptosis in cancer cells.
This PROTAC-based approach offers a potential new strategy for anticancer treatment by inducing pyroptosis.