Targeting FSP1 triggers ferroptosis in lung cancer

Area of Science:

• Oncology
• Cell Death Pathways
• Cancer Metabolism

Background:

• Oxidative stress is implicated in tumorigenesis, but its role in cancer cell death remains unclear.
• Ferroptosis, a form of regulated cell death driven by lipid peroxidation, is emerging as a potential anti-cancer strategy.
• The precise role of ferroptosis as a barrier to tumorigenesis and its therapeutic potential are largely unknown.

Purpose of the Study:

• To investigate the role of ferroptosis suppressors, glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1), in lung adenocarcinoma (LUAD) tumorigenesis.
• To determine if ferroptosis can be therapeutically leveraged in LUAD models.
• To evaluate FSP1 as a potential therapeutic target in lung cancer.

Main Methods:

• Utilized genetically-engineered mouse models (GEMMs) of LUAD for tumor-specific loss-of-function studies of GPX4 and FSP1.
• Performed lipidomic analyses to assess lipid peroxidation levels in tumors.
• Investigated the effects of genetic, dietary, and pharmacological inhibition of ferroptosis on tumor growth.
• Correlated FSP1 expression with patient survival data in LUAD.

Main Results:

• Loss of GPX4 or FSP1 led to increased lipid peroxidation and robust suppression of LUAD tumorigenesis, indicating high sensitivity to ferroptosis.
• FSP1 was essential for ferroptosis protection in vivo, but not in vitro, highlighting its physiological importance.
• Inhibition of ferroptosis rescued tumor growth in Fsp1-knockout models.
• FSP1 expression is a prognostic marker for poor survival in LUAD patients.
• Pharmacologic inhibition of FSP1 demonstrated significant therapeutic benefits in preclinical lung cancer models.

Conclusions:

• Ferroptosis suppression is crucial in vivo, and lung tumors are highly sensitive to ferroptosis.
• FSP1 plays a critical role in protecting against ferroptosis in vivo and represents a promising therapeutic target for LUAD.
• Targeting FSP1 offers a viable therapeutic strategy for lung cancer patients.