Targeting FSP1 Triggers Ferroptosis in Lung Cancer
The ferroptosis suppressor protein FSP1 plays a crucial role in protecting tumors from ferroptosis across various in vivo models and is associated with poorer outcomes in human lung adenocarcinoma. This highlights its potential as a therapeutic target for lung cancer.
Ferroptosis is a form of cell death driven by unchecked lipid peroxidation, and emerging evidence shows cancer cells are vulnerable to this process. Despite interest in exploiting ferroptosis as a novel cancer treatment, its exact role in tumor development and therapy remains unclear.
Experimental Findings in Lung Adenocarcinoma Models
Using genetically engineered mouse models, researchers conducted tumor-specific loss-of-function studies targeting two major ferroptosis suppressors: GPX4 and FSP1. They observed increased lipid peroxidation leading to strong inhibition of tumor growth, indicating lung tumors are highly sensitive to ferroptosis.
Role of FSP1 In Vivo vs In Vitro
Across several preclinical models, FSP1 was essential for protecting tumors from ferroptosis in vivo, but not in vitro, emphasizing the importance of controlling lipid peroxidation under physiological conditions.
Lipidomic Insights and Therapeutic Implications
- Lipidomic analysis showed Fsp1-knockout tumors accumulated lipid peroxides.
- Inhibiting ferroptosis through genetic, dietary, or pharmacological methods restored growth of Fsp1-knockout tumors in vivo.
"Using genetically engineered mouse models of lung adenocarcinoma, we performed tumour-specific loss-of-function studies of two key ferroptosis suppressors, GPX4 and ferroptosis suppressor protein 1 (FSP1), and observed increased lipid peroxidation and robust suppression of tumorigenesis."
"FSP1 was required for ferroptosis protection in vivo, but not in vitro, underscoring a heightened need to buffer lipid peroxidation under physiological conditions."
Author's summary: Targeting FSP1 reveals lung tumors' vulnerability to ferroptosis, offering a promising strategy for lung cancer therapy by disrupting lipid peroxide defenses in vivo.