Oncogenic RAS signaling suppresses ferroptosis via transcriptional upregulation of GCH1

Abstract Ferroptosis is an iron-dependent form of regulated cell death arising from excessive lipid peroxidation. While seminal work described that oncogenic RAS transformation drives synthetic lethal vulnerability to archetypal ferroptosis inducers including erastin (eradicator of RAS and ST-expressing cells) and RSL3 (Ras selective lethal 3), more recent work suggest that oncogenic RAS signaling may confer ferroptosis resistance. Thus, the impact of oncogenic RAS on the cellular response to ferroptosis is still unclear. Here, we provide unifying evidence across multiple cellular models that oncogenic RAS signaling suppresses ferroptosis. Using integrated proteo- and transcriptomic analyses, we uncovered that oncogenic RAS signaling upregulates the ferroptosis suppressor GTP cyclohydrolase I (GCH1) via transcriptional induction by the transcription factor ETS1 downstream of the RAS-MAPK signaling cascade. Targeted repression of Gch1 or of the tetrahydrobiopterin (BH4) synthesis pathway, which is mediated by GCH1, was sufficient to sensitize oncogenic RAS transformed cells to ferroptosis in 2D and 3D cell models, highlighting a mechanism through which RAS promotes resistance to ferroptosis induction. Furthermore, we found that GCH1 expression is clinically relevant and correlates with RAS signaling activation in human cancers. Overall, this study redefines oncogenic RAS signaling to be a ferroptosis suppressor, and identifies GCH1 as a mediator of this effect and a potential vulnerability for targeting RAS driven cancers.