Targeting Cyclin-Dependent Kinase 1 Induces Apoptosis and Cell Cycle Arrest of Activated Hepatic Stellate Cells

Liver fibrosis is the integral process of chronic liver diseases caused by multiple etiologies and characterized by excessive deposition of extracellular matrix (ECM). During liver fibrosis, hepatic stellate cells (HSCs) transform into a highly proliferative, activated state, producing various cytokines, chemokines, and ECM. However, the precise mechanisms that license HSCs into the highly proliferative state remain unclear. Cyclin-dependent kinase 1 (CDK1) is a requisite event for the transition of the G1/S and G2/M phases in eukaryotic cells. In this study, it is demonstrated that CDK1 and its activating partners, Cyclin A2 and Cyclin B1, are upregulated in both liver fibrosis/cirrhosis patient specimens and the murine hepatic fibrosis models, especially in activated HSCs. In vitro, CDK1 is upregulated in spontaneously activated HSCs, and inhibiting CDK1 with specific small-molecule inhibitors (CGP74514A, RO-3306, or Purvalanol A) orshort hairpin RNAs (shRNAs) resulted in HSC apoptosis and cell cycle arrest by regulating Survivin expression. Above all, it is illustrated that increased CDK1 expression licenses the HSCs into a highly proliferative state and can serve as a potential therapeutic target in liver fibrosis. The CDK1 complex is unregulated in hepatic stellate cells (HSCs) during liver fibrosis. Inhibiting CDK1 activity with CDK1-specific inhibitors (CGP74514A, RO-3306, or Purvalanol A) or knocking down CDK1 expression in HSCs induces HSC apoptosis and cell cycle arrest through suppressing Survivin. CDK1 may serve as a potential anti-fibrotic target in liver fibrosis.image