Phytosphingosine Alleviates Cigarette Smoke‐Induced Bronchial Epithelial Cell Senescence in Chronic Obstructive Pulmonary Disease by Targeting the Free Fatty Acid Receptor 4
Why this work is in the frame
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Bibliographic record
Abstract
Chronic obstructive pulmonary disease (COPD) is a complex and irreversible respiratory disorder with a poor prognosis and a lack of effective pharmaceutical treatment. Our previous metabolomics study identified phytosphingosine (PHS) as a key differential metabolite in COPD that is positively correlated with lung function. In this study, we investigated the bioactive effects of PHS on experimental COPD and its underlying mechanisms using cigarette smoke (CS)-induced mouse and cell models. We found that administering PHS improved CS-induced lung dysfunction, emphysema, and airway inflammation by reducing cellular senescence and the senescence-associated secretory phenotype in bronchial epithelium. Mechanistically, PHS interacted with the free fatty acid receptor 4 (FFAR4) and upregulated its expression, leading to the modulation of STIP1 homology and U-Box containing protein 1 (STUB1) downstream, which controlled the ubiquitination levels of P53 and mitigated cellular senescence. Moreover, both FFAR4 overexpression through intratracheal injection of adeno-associated virus and the administration of the FFAR4 agonist TUG891 showed therapeutic effects on CS-induced lung damage. Our results highlight the beneficial impacts of PHS in experimental COPD mediated through the FFAR4 receptor, protecting against CS-induced bronchial epithelial cell senescence and suggesting PHS as a promising therapeutic agent for COPD.
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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 | 0.001 | 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