Benvitimod inhibits MCM6-meditated proliferation of keratinocytes by regulating the JAK/STAT3 pathway

Abstract

BackgroundBenvitimod (Tapinarof), as a small-molecule topical therapeutical aryl hydrocarbon receptor (AHR)-modulating agent, is in clinical development for treating psoriasis and atopic dermatitis. Benvitimod reduces proinflammatory cytokines in psoriasis by specifically binding and activation of AHR. However, whether benvitimod can inhibit keratinocyte proliferation remains unclear. Minichromosome maintenance protein 6 (MCM6) is a key element of the prereplication complex (pre-RC) assembly which is one of the essential steps in the initiation of DNA replication for cell proliferation. ObjectivesThis study aimed to determine whether benvitimod could reduce the excessive proliferation of psoriatic keratinocytes by inhibiting MCM6. MethodsWe examined the inhibitory effect of benvitimod on MCM6-mediated proliferation of keratinocytes by HaCaT cells in vitro and an IMQ-induced psoriatic model of mice in vivo. ResultsEpidermal MCM6 expression was enhanced in the skin lesions of psoriatic patients. The experiments further revealed that MCM6 was required for the proliferation of keratinocytes and governed by the IL-22/STAT3 pathway. In addition, the antiproliferation effect of benvitimod is achieved by the inhibition of p-JAK1 and p-JAK2, which further restrained the activation of STAT3 in keratinocytes. Lastly, benvitimod could repressed imiquimod-induced skin lesions and the expression of epidermal MCM6 and p-STAT3 in mice. Moreover, knockdown of AHR in keratinocytes enhanced the activation of JAK1 and JAK2. ConclusionThe findings reveal that benvitimod could decrease MCM6-mediated proliferation of keratinocytes by affecting the JAK/STAT3 pathway, thereby serving as a new treatment modality for psoriasis.