Inhibition of KPNA2 by ivermectin reduces E2F1 nuclear translocation to attenuate keratinocyte proliferation and ameliorate psoriasis-like lesions

Psoriasis is a chronic, immune-mediated skin disease with a significant global prevalence. Karyopherin subunit alpha 2 (KPNA2), a nuclear transport protein involved in cellular activities such as differentiation, proliferation, Apoptosis, and immune response, has emerged as a potential biomarker in several diseases. Our study found that KPNA2 was significantly upregulated in psoriasis patients and in imiquimod (IMQ)-induced psoriasis mouse models by bioinformatics and molecular biotechnology. In vivo, treatment with ivermectin, a KPNA2 inhibitor, significantly improved psoriasis symptoms in mice as evidenced by reduced erythema, desquamation, and skin thickness. Histopathological staining revealed decreased expression of KPNA2, K17, and Ki67 in ivermectin-treated mice, suggesting reduced abnormal differentiation and proliferation of keratinocytes. Transcriptome data and immunoblotting analysis showed that KPNA2 inhibition reduced inflammation and keratinocyte proliferation and differentiation in IMQ-induced mice. In vitro, EdU (5-ethynyl-2'-deoxyuridine) and flow cytometry experiments demonstrated that the downregulation of KPNA2 expression in HaCaT cells was capable of inhibiting the EGF (Epidermal Growth Factor)-induced activation of Akt/STAT3 signaling and keratinocytes proliferation. In addition, nuclear-cytoplasmic protein separation and immunofluorescence localization experiments showed that KPNA2 inhibition affected the nuclear translocation of E2F transcription factor 1 (E2F1), a process critical for keratinocyte proliferation. This study elucidated the role of KPNA2 in the pathogenesis of psoriasis and highlighted its potential as a target for future psoriasis therapies. These findings provide new insights into targeted therapy for psoriasis and have significant implications for future clinical treatment.