*Purpose: Hepatic ischemia/reperfusion injury (IRI), an exogenous antigen-independent local inflammation response, occurs in multiple clinical settings including liver transplantation, hepatic resection, trauma, and shock. The cyclin-dependent kinase 2 (CDK2) acts as a pivotal regulator of cell cycle and proliferation.

*Methods: This study examined the function and therapeutic potential of CDK2 inhibition in murine model of liver “warm” ischemia IRI.

*Results: Liver IR triggered intrinsic CDK2 expression, peaking by 0.5h of reperfusion, and maintaining a high level throughout 1h-24h. Interestingly, immunofluorescence staining indicated colocalization of CDK2 and CD68, which determined CDK2 expression in CD68⁺ macrophages in the liver with 90min of ischemia and 6h of reperfusion. We then employed Roscovitine, a specific CDK2 inhibitor, which showed therapeutic potential in leukemia, herpes simplex infection, HIV infection, and breast cancer. Strikingly, administration of Roscovitine prevented liver IR mediated damage with abolished serum ALT levels and reserved liver pathology (i.e., no edema, congestion or necrosis). CDK2 inhibition mediated liver protection was accompanied by decreased macrophage/neutrophil infiltration, diminished hepatocyte apoptosis, abolished TLR4 signaling and downstream gene inductions (CXCL-10, TNF-a, IL-1β and IL-6), yet augmented IL-10 expression. In vitro, CDK2 inhibition by Roscovitine suppressed macrophage TLR4 activation, and further depressed downstream inflammatory signaling (MyD88, IRF3, p38, JNK and ERK).

*Conclusions: Our novel findings document the critical role of CDK2 in hepatic homeostasis and cytoprotection in liver IRI. As CDK2 inhibition regulated local inflammation and prevented hepatocyte death, these results provide the rationale for novel therapeutic approaches to combat liver IRI in transplant patients.

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