Sibiriline, a novel dual inhibitor of necroptosis and ferroptosis, prevents RIPK1 kinase activity and (phospho)lipid peroxidation as a potential therapeutic strategy
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
Abstract In the past two decades, various non-apoptotic pathways of regulated cell death have been identified; a small subset of these, including necroptosis and ferroptosis, manifests the phenotypic features of necrotic death. These two regulated necroses are being extensively studied because of their putative roles in severe acute and chronic pathologies. Moreover, as these regulated necrotic pathways are coactivated in a number of common pathologies, the development of multi-target directed ligands (that is, the use of a polypharmacological strategy) is a path-breaking avenue of research. In this study, we determined that the 7-azaindole derivative, sibiriline, inhibited both RIPK1-driven necroptosis (induced by Tumor Necrosis Factor-α) and ferroptosis (triggered by various classes of ferroptosis inducers), with EC 50 s against each in the µM range. We next performed a combined large-scale transcriptomic study in order to determine the molecular mechanisms of action of sibiriline. We identified the stress response protein heme oxygenase-1 (HMOX1) as the main biomarker of ferroptosis inhibition by sibiriline. We hypothesized that this compound reacts as an antioxidant to block ferroptosis; indeed, we found that sibiriline inhibits lipid peroxidation by trapping phospholipid-derived peroxyl radicals as a radical-trapping antioxidant (RTA). Taken together, these results show that sibiriline is a new dual inhibitor of necroptosis and ferroptosis cell death pathways; it works by inhibition of both RIPK1 kinase and (phospho)lipid peroxidation. We also demonstrate the in vitro efficacy of sibiriline to inhibit cell death in cell-based models of Parkinson’s disease and cystic fibrosis. These findings shed light on the high therapeutic potency of RIPK1 inhibitors with RTA activity.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.000 | 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 it