| RRC ID |
90008
|
| 著者 |
Hashimoto K, Arioka M, Morimoto T, Wang Y, Ito K, Ishikane S, Yatera K, Takahashi-Yanaga F.
|
| タイトル |
OSU-03012 mitigates pulmonary fibrosis by targeting ECM proteins via suppression of S6K-mediated translation and acceleration of MMP-driven clearance.
|
| ジャーナル |
Biomed Pharmacother
|
| Abstract |
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease. Currently available anti-fibrotic therapies are limited to slowing lung function decline; however, inducing the resolution of fibrotic lesions remains highly challenging. This study investigated the anti-fibrotic potential and underlying molecular mechanisms of OSU-03012 action, a celecoxib derivative that inhibits Akt activity without targeting cyclooxygenase. To evaluate the in vivo effects of OSU-03012 on preventative and therapeutic effects, a bleomycin-induced pulmonary fibrosis mouse model was used. Micro-computed tomography and histopathological analyses demonstrated that OSU-03012 administration not only prevented fibrotic progression but also induced significant therapeutic effect in vivo. In vitro mechanistic studies were performed using MRC-5 human lung fibroblasts stimulated with transforming growth factor-β1. OSU-03012 exhibited dual anti-fibrotic effects on extracellular matrix (ECM) dynamics. First, it potently suppressed de novo ECM production at the translational level via selective inhibition of the p70 ribosomal S6 kinase. Second, it actively promoted ECM degradation by upregulating matrix metalloproteinase expression through the activation of the ERK and JNK pathways. Collectively, these findings demonstrate that OSU-03012 exerts potent anti-fibrotic and regressive effects by targeting ECM proteins through the inhibition of ECM component translation and the promotion of ECM degradation. Thus, OSU-03012 represents a novel and promising therapeutic candidate capable of overcoming the critical limitations of current IPF and pulmonary fibrosis treatments.
|
| 巻・号 |
204
|
| ページ |
119905
|
| 公開日 |
2026-9-24
|
| DOI |
10.1016/j.biopha.2026.119905
|
| PII |
S0753-3322(26)00941-8
|
| PMID |
42785080
|
| リソース情報 |
| ヒト・動物細胞 |
MRC-5(RCB0218) |
