Small-Molecule Ferritin Degrader as a Pyroptosis Inducer

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.