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Updated: Aug 1, 2025
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Published on: March 15, 2024
Small-Molecule Ferritin Degrader as a Pyroptosis Inducer
Yu Chen1,2,3, Wen Li1, Song Kwon1
1Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.
Abstract:
Exploring the response of malignant cells to intracellular metabolic stress is critical for understanding pathologic processes and developing anticancer therapies. Herein, we developed ferritin-targeting proteolysis targeting chimeras (PROTACs) to establish the iron excess stress inside cancer cells and investigated subsequent cellular behaviors. We conjugated oleic acid that binds to the ferritin dimer to the ligand of von Hippel-Lindau (VHL) E3 ligase through an alkyl linker. The screened chimera, DeFer-2, degraded ferritin and then rapidly elevated the free iron content, thereby initiating the caspase 3-GSDME-mediated pyroptosis in cancer cells rather than typical ferroptosis that is always associated with iron ion overload. According to its structural and physicochemical characteristics, DeFer-2 was loaded into a tailored albumin-based nano-formulation, which substantially inhibited tumor growth and prolonged the survival time of mice bearing B16F10 subcutaneous tumors with negligible adverse effects. This study developed a ferritin-targeting PROTAC for iron overload stress, revealed iron metabolic dysregulation-mediated pyroptosis, and provided a PROTAC-based pyroptosis inducer for anticancer treatment.
Insights
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.
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.
