Co-disruption of GPX4 and DHODH Ferroptosis Defense Systems via Excipient-Free Self-Assembled Nanoassemblies for...

Area of Science:

• Biomedical Engineering
• Oncology
• Nanotechnology

Background:

• Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to its aggressive nature and limited treatment options.
• Ferroptosis, a form of regulated cell death dependent on iron and lipid peroxidation, is an emerging strategy against TNBC.
• Tumor cells possess defense mechanisms, such as glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), that confer resistance to ferroptosis.

Purpose of the Study:

• To develop a tumor-targeting, excipient-free nanoassembly (DoT) for enhanced ferroptosis induction in TNBC.
• To investigate the synergistic effect of doxorubicin (DOX) and teriflunomide (Tfm) within the DoT nanoassembly.
• To overcome TNBC's resistance to ferroptosis by co-disrupting its defense systems.

Main Methods:

• Self-assembly of doxorubicin (DOX) and teriflunomide (Tfm) into tumor-targeting nanoassemblies (DoT).
• Inhibition of the GPX4 defense system via Nrf2 inhibition by DOX.
• Suppression of the DHODH system and antioxidant capacity by Tfm.

Main Results:

• DoT nanoassemblies effectively induced ferroptosis in TNBC cells.
• DOX disrupted the GPX4 system and initiated lipid peroxidation.
• Tfm further compromised ferroptosis defenses, leading to robust cell death.
• The co-disruption strategy demonstrated significant potential for TNBC treatment.

Conclusions:

• A synergistic co-disruption strategy targeting dual ferroptosis defense systems was successfully developed.
• The DoT nanoassembly represents a promising therapeutic approach for TNBC.
• This strategy holds potential for future clinical applications in treating aggressive breast cancers.