Oncogenic RAS signaling is a tumor cell-intrinsic determinant of ferroptosis suppression via induction of the GCH1/BH4 axis
Bibliographic record
Abstract
Abstract Ferroptosis is an iron-dependent form of regulated cell death arising from excessive lipid peroxidation. The role of oncogenic RAS signaling in modulating the cellular response to ferroptosis is controversial. While seminal studies described that oncogenic RAS transformation drives a 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 expression on ferroptosis sensitivity is still poorly understood. Here, using orthogonal cellular systems across multiple classes of ferroptosis- inducing agents, as well as in silico therapeutic drug-response analyses, we provide unifying evidence that oncogenic RAS signaling suppresses ferroptosis. Integrated proteo- and transcriptomic analyses in oncogenic RAS-transformed cells further uncovered that 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 Gch1-controlled tetrahydrobiopterin (BH4) synthesis pathway is sufficient to sensitize RAS-mutant cell lines to ferroptosis in 2D and 3D cell models, as well as in tumor organoids and tumor xenografts, 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 clinical target for the sensitization of RAS-driven cancers to ferroptosis-inducing agents. Significance Statement Although it is commonly accepted that ferroptosis induction is a mutant RAS-selective lethality, accumulating evidence suggests that oncogenic RAS protects cells against this form of cell death. However, a systematic survey establishing the relationship between RAS and ferroptosis sensitivity is lacking, and the molecular mechanisms this entails are still poorly understood. Here, we report across RAS-mutant isoforms, in diverse cellular models, and using multiple ferroptosis-inducing compounds that oncogenic RAS consistently suppresses ferroptosis. Further, we show that oncogenic RAS-mediated ferroptosis suppression is attributed to the upregulation of GCH1 and its downstream metabolite, tetrahydrobiopterin. Our study delivers a shift towards a new paradigm in which oncogenic RAS confers ferroptosis resistance, and a potential clinical strategy to re-engage ferroptosis sensitivity in RAS-driven cancers.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".