Cyclin-Dependent kinase 9 (CDK9) inhibitor Atuveciclib ameliorates Imiquimod-Induced Psoriasis-Like dermatitis in mice by inhibiting various inflammation factors via STAT3 signaling pathway

Abstract

Psoriasis is a chronic, autoimmune skin disease characterized by the deregulated secretion of inflammatory factors in multiple organs. The aberrant activation of signal transducer and activator of transcription 3 (STAT3) signaling pathway mediated by cyclin-dependent kinase 9 (CDK9) is vital for the pathology of psoriasis, leading to the accumulation of inflammatory factors and the progression of skin damage. In this study, we explored the effect of CDK9 inhibition on attenuating the secretion of inflammatory factors and alleviating skin damage in psoriasis models both in vitro and in vivo. Results showed that Atuveciclib, a highly selective CDK9 inhibitor, significantly relieved skin lesions in Imiquimod (IMQ)-induced mice models by lowering the expression of CDK9 and p-RNA Pol II Ser2. Meanwhile, Atuveciclib significantly inhibited STAT3 phosphorylation in mice skin and reduced the levels of key inflammatory cytokines in mice skin, plasma and spleen. In addition to suppressing the secretion of inflammatory cytokines, Atuveciclib ablated the activation of STAT3 induced by tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ). Overall, our findings indicated that the overexpression and hyperfunction of CDK9 promote the progression of psoriasis. Moreover, Atuveciclib interfered with the abnormal STAT3 signaling pathway through the inhibition of CDK9, which ultimately ameliorated psoriatic-like skin inflammation. These suggested that CDK9 inhibition is a potential strategy for batting psoriasis.