Background and Aims Abnormal epigenetic changes are involved in over-activated pathogenic IFN signalling in SLE. However, the mechanisms are still not clear. We tried to identify novel epigenetic regulators of IFN signalling pathways in SLE.
Methods We screened 463 epigenetic regulatory genes using a siRNA library in a high-throughput ISRE-luciferase assay. Q-PCR and Western blot were used to study the function of targeted genes.
Results Among those genes which significantly enhanced or inhibited ISRE activity, CDK1 had a differential expression in PBMCs and renal biopsies between SLE patients and healthy controls and was positively correlated with “IFN scores” and disease activities of SLE patients. We revealed that the expression of ISGs and phosphorylation of STAT1 could be reduced by knocking down CDK1, while over-expression of CDK1 produced an opposite effect. As specific inhibitors of IFN pathway has emerged as a promising treatment for SLE and CDK1 inhibitors are being on trial for some types of cancer, we wondered whether CDK1 inhibitor could be a potential repositioning drug for SLE. We found a CDK1 inhibitor, RO-3306, could alleviate FN in PBMCs from 5 SLE patients who had high IFN scores. We found that RO-3306 significantly reduced ISGs expression in these cells. Our preliminary data further showed that RO-3306 could reduce proteinuria in SLE mouse model.
Conclusions We proposed that CDK1 is a novel positive regulator of IFN signalling pathway, over-expression of CDK1 in SLE might contribute to the over-activated IFN signalling and inhibition of CDK1 could be used to interfere abnormal IFN signalling in SLE.
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