Abstract
Pulmonary fibrosis (PF) is a high-mortality lung disease with limited treatment options, highlighting the need for new therapies. Cyclin-dependent kinase 8 (CDK8) is a promising target due to its role in regulating transcription via the TGF-β/Smad pathway, though CDK8 inhibitors have not been thoroughly studied for PF. This study aims to evaluate the potential of E966–0530–45418, a novel CDK8 inhibitor, in mitigating PF progression and explores its underlying mechanisms. We discovered that CDK8 is upregulated in lung tissues from idiopathic pulmonary fibrosis patients and in a bleomycin-induced PF mouse model. Our study further revealed that E966–0530–45418 inhibits PF progression by attenuating the activity of the transcription factor Smad3, which is involved in TGF-β1/Smad signaling, along with RNA polymerase II to downregulate fibrosis-associated protein expression in alveolar epithelia and lung fibroblasts and consequently mitigate myofibroblast differentiation and collagen deposition. E966–0530– 45418 also blocks STAT3 signaling to obstruct M2 macrophage polarization, further suppressing PF progression. Moreover, E966–0530–45418 administration ameliorated lung function deterioration and lung parenchymal destruction in the bleomycin-induced PF mouse model. These findings indicate that E966–0530–45418 holds promise as a pioneering CDK8 inhibitor for treating PF.
Original language | English |
---|---|
Pages (from-to) | 685-707 |
Number of pages | 23 |
Journal | International Journal of Biological Sciences |
Volume | 21 |
Issue number | 2 |
DOIs | |
Publication status | Published - 2025 |
Keywords
- cyclin-dependent kinase 8
- drug discovery
- pulmonary fibrosis
- TGFβ1/Smad signaling
- transcriptional regulation
ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Applied Microbiology and Biotechnology
- Molecular Biology
- Developmental Biology
- Cell Biology