Late Breaking Abstract - Pharmacological inhibition of Epac1 protects against pulmonary fibrosis by blocking FoxO3a neddylation
Bibliographic record
Abstract
<bold>Background:</bold> Idiopathic Pulmonary Fibrosis (IPF) is marked by progressive lung scarring with no existing cure, emphasizing the need for new therapeutic targets. Current evidence suggests that cyclic adenosine monophosphate (cAMP) mitigates lung fibroblast proliferation via the PKA pathway, but the impact of Epac1, a cAMP-activated protein, on IPF remains unexplored. <bold>Objective:</bold> To investigate the role of Epac1 in IPF progression. <bold>Methods:</bold> We examined lung samples from IPF patients and controls, and from a bleomycin-induced mouse model of pulmonary fibrosis (PF). Epac1’s effects were analyzed in knock-out mice and with viral vectors. The Epac1-specific small compound inhibitor AM-001 was evaluated in vitro using lung fibroblasts from IPF patients, in vivo in bleomycin mice, and ex vivo in IPF precision cut lung slices. <bold>Results:</bold> Increased Epac1 expression was observed in IPF patient lung tissues, fibrotic fibroblasts, and bleomycin-challenged mice. Pharmacological inhibition of Epac1 with AM-001 reduced proliferation in fibroblasts and expression of pro-fibrotic markers. Epac1-specific inhibition protected against bleomycin-induced lung fibrosis, suggesting significant therapeutic potential. Global gene expression profiling indicated reduced neddylation pathway elements in Epac1-deficient fibroblasts and human-derived lung cells. The protective effects may involve inhibiting the neddylation pathway and NEDD8 activation, thus reducing the degradation of FoxO3a. <bold>Conclusions:</bold> Our findings demonstrate that Epac1 regulates fibroblast activity in pulmonary fibrosis, and that targeting Epac1 with a pharmacological inhibitor AM-001 offers a promising therapeutic approach for treating IPF.
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How this classification was reachedexpand
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) | 0.000 | 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 | 0.001 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".