Pharmacological inhibition of Epac1 protects against pulmonary fibrosis by blocking FoxO3a neddylation
Bibliographic record
Abstract
Background Idiopathic pulmonary fibrosis (IPF) is marked by progressive lung scarring with no existing cure, emphasising the need for new therapeutic targets. Current evidence suggests that cyclic adenosine monophosphate (cAMP) mitigates lung fibroblast proliferation via the protein kinase A pathway, but the impact of exchange proteins directly activated by cAMP 1 (Epac1) on IPF remains unexplored. Objective To investigate the role of Epac1 in IPF progression. Methods We examined lung samples from IPF patients and controls, and from a bleomycin-induced mouse model of pulmonary fibrosis. The effects of Epac were analysed in knockout mice and through modulation using viral vectors. The Epac1-specific small compound inhibitor AM-001 was evaluated in vitro using lung fibroblasts from patients with IPF, in vivo in bleomycin mice and ex vivo in IPF precision-cut lung slices. Results Increased Epac1 expression was observed in lung tissues from IPF patients, fibrotic fibroblasts and bleomycin-challenged mice. Genetic or pharmacological inhibition of Epac1 with AM-001 decreased proliferation in normal and IPF fibroblasts, and reduced expression of profibrotic markers such as α-smooth muscle actin, transforming growth factor-β/SMAD family member 2/3, and interleukin-6/signal transducer and activator of transcription 3 pathways. Epac1-specific inhibition consistently protected against bleomycin-induced lung injury and fibrosis, suggesting significant therapeutic potential. Global gene expression profiling indicated a reduced profibrotic gene signature and neddylation pathway components in Epac1-deficient fibroblasts and human-derived lung cells. Mechanistically, the protective effects may involve inhibiting the neddylation pathway and preventing neural precursor cell expressed, developmentally downregulated 8 (NEDD8) activation, which in turn reduces the degradation of forkhead box protein O3 by NEDD8. Additionally, these effects may be enhanced while also limiting the proliferation of lung-infiltrating monocytes. Conclusions Our findings demonstrate that Epac1 regulates fibroblast activity in pulmonary fibrosis, and that targeting Epac1 with the pharmacological specific inhibitor AM-001 offers a promising therapeutic approach for treating IPF disease.
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.
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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".