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 triggered by uncontrolled lipid peroxidation1–3. Despite broad enthusiasm about harnessing ferroptosis as a novel anti-cancer strategy, whether ferroptosis is a barrier to tumorigenesis and if it can be leveraged therapeutically remains unknown4,5. 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)6,7 and ferroptosis suppressor protein 1 (Fsp1)8,9, and observed increased lipid peroxidation 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 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 Fsp1KO 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. 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 in lung cancer patients. Competing Interest Statement T.P. received funding from Pfizer Medical Education Group, Dracen Pharmaceuticals, Kymera Therapeutics, Bristol Myers Squibb, and Agios Pharmaceuticals not related to the submitted work. M.C. is a co-founder and shareholder of ROSCUE Therapeutics GmbH. M.C. and T.N. have filed patents for some of the compounds described herein. Footnotes This version mirrors the submission of the manuscript to the journal after editorial revisions.