PPARγ Antagonists Exhibit Antitumor Effects by Regulating Ferroptosis and Disulfidptosis

Area of Science:

• Oncology
• Molecular Biology
• Cell Death Mechanisms

Background:

• Oral squamous cell carcinoma (OSCC) is a major head and neck cancer with poor outcomes.
• Peroxisome proliferator-activated receptor gamma (PPARγ) is implicated in tumor development, but its precise role in OSCC is unclear.

Purpose of the Study:

• To investigate the role of PPARγ in OSCC development and explore its potential as a therapeutic target.
• To elucidate the mechanisms by which PPARγ inhibition affects cell death pathways in OSCC.

Main Methods:

• Transcriptome sequencing, transmission electron microscopy, iron detection assays, qPCR, and Western blotting were employed.
• In vivo studies utilized a mouse tongue orthotopic transplantation tumor model with flow cytometry and immunohistochemical staining.

Main Results:

• PPARγ inhibition triggered ferroptosis and disulfidptosis in OSCC cells.
• PPARγ inhibition upregulated HMOX1 (promoting ferroptosis) and SLC7A11 (promoting disulfidptosis).
• Inhibition of PPARγ led to increased cDC and CD8+ T cell aggregation and suppressed OSCC progression in vivo.

Conclusions:

• PPARγ plays a critical role in regulating ferroptosis and disulfidptosis in OSCC.
• Targeting PPARγ represents a promising therapeutic strategy for oral squamous cell carcinoma by inducing dual cell death and enhancing anti-tumor immunity.