Targeting CDK7/12/13 functional synergism reverses myofibroblast activation and ameliorates lung fibrosis.

Lung fibrosis, characterized by persistent deposition of extracellular matrix to alveolar areas, is a progressive fibrotic disease, which leads to lung function decline and mortality. At the cellular level, myofibroblast activation and proliferation are the central cellular events of lung fibrosis. Here, through a functional genetics screen, we identify cyclin-dependent kinase 13 (CDK13) as a regulator of pro-fibrotic gene expression. Further analyses show that CDK13 cooperates with CDK12 and CDK7 to synergistically induce myofibroblast activation, contractility, and proliferation. Pharmacological inhibition of CDK7/12/13 by a small molecule inhibitor, THZ1, induces myofibroblast reprogramming and reverses myofibroblast activation in vitro. Consistent with these findings, we show that THZ1 ameliorates lung fibrosis and blocks myofibroblast activation and proliferation in the bleomycin model. These results reveal CDK7/12/13 as the previously unrecognized determinants of myofibroblast activation and lung fibrosis and support their functional synergism as a tractable therapeutic target for patients with fibrotic lung diseases.