The Kv1.3 blocker PAP‑1 alleviates psoriasis‑like dermatitis in rats via suppressing inflammation and angiogenesis

Psoriasis is a chronic inflammatory skin disorder driven by epidermal hyperplasia, immune infiltration, and pathological angiogenesis. PAP‑1, a selective Kv1.3 channel blocker, exhibits therapeutic potential, though its underlying mechanisms remain incompletely understood. Here, we show that both preventive and therapeutic administration of PAP‑1 markedly attenuates imiquimod (IMQ)-induced psoriasis‑like skin lesions and reduces splenomegaly in male rats. RNA sequencing revealed that PAP-1 downregulated genes associated with inflammation and angiogenesis, accompanied by decreased levels of pro-inflammatory cytokines and vascular markers. PAP-1 also inhibited VEGF-A-induced HUVEC proliferation, migration, invasion, and tube formation. Mechanistically, PAP-1 not only blocked Kv1.3 currents, but also suppressed Kv1.3 expression in the skin of IMQ-induced psoriasis-like male rats and VEGF-A-induced HUVECs. Cryo-EM structural analysis revealed that PAP-1 binds within the central cavity of Kv1.3, beneath the selectivity filter, in an inactivated state. These results establish that preventive and therapeutic PAP-1 alleviates psoriasis-like dermatitis via dual anti-inflammatory and anti-angiogenic mechanisms, supporting its further therapeutic development.