Targeting FSP1 triggers ferroptosis in lung cancer

ABSTRACT 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 (Fsp1 KO ) 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.