Liver X receptors agonist T0901317 exerts ferroptosis sensitization in cancer

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Ferroptosis demonstrates anticancer effects across various tumors.
• Improving tumor susceptibility to ferroptosis is crucial for overcoming drug resistance and treating refractory cancers.

Purpose of the Study:

• To investigate the synergistic anticancer effects of combining LXRS agonist T0901317 with ferroptosis inducers (FINs).
• To elucidate the role of Glutathione peroxidase 4 (GPX4) in T0901317-mediated ferroptotic sensitization.

Main Methods:

• Co-treatment of cancer cells with T0901317 and FINs.
• Assessment of cell proliferation inhibition and lipid peroxide levels.
• Evaluation of GPX4's role using overexpression and specific ferroptosis inhibitors.
• In vivo validation using a xenograft tumor model.

Main Results:

• Combined treatment significantly inhibited cancer cell proliferation.
• Inhibition was reversed by ferroptosis inhibitors and associated with elevated lipid peroxides.
• GPX4 overexpression reversed the combined anticancer effect, confirming its regulatory role.
• In vivo xenograft models confirmed T0901317's ferroptotic sensitization effect.

Conclusions:

• Co-treatment with T0901317 and FINs effectively induces ferroptosis and inhibits cancer cell growth.
• This drug combination strategy, targeting ferroptosis, presents a promising therapeutic option for cancer treatment, particularly for resistant and refractory tumors.