Exploiting Cancer Vulnerabilities by Blocking of the DHODH and GPX4 Pathways: A Multifunctional Bodipy/PROTAC...

Area of Science:

• Biomedical Engineering
• Cancer Therapy
• Nanotechnology

Background:

• Ferroptosis, a programmed cell death pathway, is crucial in disease pathogenesis.
• Dihydroorotate dehydrogenase (DHODH) and glutathione peroxidase 4 (GPX4) are critical regulators of ferroptosis resistance.
• Targeting DHODH and GPX4 offers a promising strategy for synergistic cancer therapy.

Purpose of the Study:

• To develop a multifunctional nanoagent (BPNpro) for synergistic ferroptosis induction in cancer therapy.
• To investigate the combined inhibition of GPX4 and DHODH using a novel nanodelivery system.

Main Methods:

• A nanoagent (BPNpro) was synthesized, encapsulating a GPX4-targeting boron dipyrromethene (Bodipy) probe (BP) within a thermoresponsive liposome.
• The nanoagent featured a cathepsin B (CatB)-cleavable PROTAC peptide (DPCP) for DHODH targeting on its surface.
• Near-infrared (NIR) photoirradiation triggered BP release, while CatB activation released DPCP for targeted protein inhibition.

Main Results:

• BPNpro successfully released BP and DPCP in tumor cells upon NIR irradiation and CatB activation.
• BP covalently inhibited GPX4 activity, and DPCP degraded DHODH.
• The synergistic inhibition of GPX4 and DHODH induced significant ferroptosis and cell death.
• In vivo and in vitro studies demonstrated potent antitumor effects of the BPNpro nanoagent.

Conclusions:

• The developed multifunctional nanoagent effectively induces ferroptosis through synergistic targeting of GPX4 and DHODH.
• This approach represents a promising strategy for advanced cancer therapy with significant antitumor efficacy.