Targeting FSP1 triggers ferroptosis in lung cancer

Pre-clinical and clinical studies have demonstrated how dietary antioxidants or mutations activating antioxidant metabolism promote cancer, highlighting a central role oxidative stress in tumorigenesis. However, it is unclear if oxidative stress ultimately increases to a point of cell death. Emerging evidence indicates that cancer cells are susceptible to ferroptosis, a form of cell death that is triggered by uncontrolled lipid peroxidation. Despite broad enthusiasm about harnessing ferroptosis as a novel anti-cancer strategy, it remains unknown whether ferroptosis is a barrier to tumorigenesis and if it can be leveraged therapeutically. Using genetically-engineered mouse models (GEMMs) of lung adenocarcinoma (LUAD), we performed tumor specific loss-of-function studies of the two key ferroptosis suppressors, glutathione peroxidase 4 (Gpx4) and ferroptosis suppressor protein 1 (Fsp1), and observed increased lipid peroxidation, ferroptosis and robust suppression of tumorigenesis, suggesting that lung tumors are highly sensitive to ferroptosis. Furthermore, across multiple pre-clinical models, we found that FSP1 was selectively required for ferroptosis protection in vivo, but not in vitro, underscoring a heightened need to buffer lipid peroxidation under physiological conditions. Lipidomic analyses revealed that Fsp1-knockout (Fsp1KO) tumors had an accumulation of lipid peroxides, and inhibition of ferroptosis with genetic, dietary, or pharmacological approaches effectively restored the growth of Fsp1 KO tumors in vivo. Unlike GPX4, FSP1 expression was prognostic for disease progression and poorer survival in LUAD patients, highlighting its potential as a viable therapeutic target. Moreover, given the critical role of GPX4 in multiple tissues, there is a greater therapeutic window for targeting FSP1. To this end, we demonstrated that pharmacologic inhibition of FSP1 had significant therapeutic benefit in pre-clinical lung cancer models. Our studies highlight the importance of ferroptosis suppression in vivo and pave the way for FSP1 inhibition as a therapeutic strategy to improve disease outcome in lung cancer patients.