Inhibition of CDC25C attenuates IL-17A-driven keratinocyte hyperproliferation and psoriasis progression.

Abstract

Psoriasis is an IL-17-driven chronic inflammatory skin disease characterized by excessive keratinocyte proliferation. Although anti-IL-17 biologics have shown substantial clinical benefit, incomplete efficacy and disease recurrence remain common, underscoring the need to identify additional downstream targets. We previously identified CDC25C as a key effector in a non-canonical IL-17A pathway that promotes epidermal hyperplasia. Here, we explored its therapeutic potential. Analysis of single-cell RNA-seq datasets from psoriatic patients revealed that CDC25C was significantly upregulated in lesional skin and selectively enriched in proliferative and inflammatory epidermal keratinocyte subsets. In vitro, IL-17A increased CDC25C expression and promoted keratinocytes proliferation. CDC25C inhibition with NSC95397 induced G2-phase arrest and significantly suppressed keratinocyte hyperproliferation and migration. Notably, it did not impair classical IL-17-induced proinflammatory factors expression, such as IL6 and CSF1. In an IMQ-induced psoriasis-like mouse model, CDC25C inhibition markedly alleviated epidermal hyperplasia, splenomegaly, and keratinocyte proliferation without affecting upstream cytokines such as Il-6 or Tnf. This selective inhibition profile is consistent with the operation of CDC25C within a non-canonical IL-17 signaling pathway. In addition, prophylactic administration of NSC95397 prior to disease induction provided stronger protection than therapeutic treatment, suggesting the role of CDC25C during early disease initiation. Together, these findings identify CDC25C as a key mediator of IL-17-driven keratinocyte hyperproliferation and validate it as a promising therapeutic strategy.