UBE2M-mediated EGFR neddylation drives keratinocyte proliferation in psoriasis

Basal keratinocytes (KCs) exhibit enhanced proliferative activity alongside severely impaired differentiation in psoriasis. Accumulating evidence has implicated dysregulation of the neddylation pathway in various human diseases; however, its role in psoriasis remains largely unexplored. In this study, we assessed global neddylation levels and the expression of neddylation-associated enzymes in both human psoriatic lesions and imiquimod (IMQ)-induced murine models of psoriasis. Our results revealed a significant upregulation of the E2-conjugating enzyme UBE2M in psoriatic lesions. UBE2M promotes psoriatic pathogenesis by enhancing keratinocyte proliferation and inflammatory responses. Both genetic and pharmacological inhibition of UBE2M suppressed psoriasis-like development in vitro and in vivo. Mechanistically, we showed that UBE2M enhances keratinocyte proliferation and migration by increasing neddylation-mediated modification of EGFR, thereby stabilizing and activating EGFR. The results highlight the therapeutic potential of targeting UBE2M and neddylation in psoriasis treatment.