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.