Topical Application of Artesunate Ameliorates Psoriatic Keratinization and Inflammation via Molecular Modulations Based on Both Human and Mouse Models

Artesunate (ART), a drug renowned for its anti-inflammatory and antiproliferative properties, shows promise in psoriasis treatment by potentially modulating autoimmune responses. This study evaluated the efficacy of ART in an imiquimod (IMQ)-induced mouse psoriatic model via topical application and intraperitoneal injection, alongside in vitro investigations using a HaCaT cell-based model. Our results demonstrated that topical ART application significantly alleviated psoriatic inflammation and hyperkeratinization and reduced Th17 and IL-17A⁺ γδ T-cell infiltration, proving superior to intraperitoneal administration. Notably, ART markedly suppressed the expression of the pathogenic keratins Krt16 and Krt17, which are crucial in psoriasis pathogenesis. In vitro, ART not only enhanced the anti-inflammatory effect of dexamethasone (DEX) by reducing pro-inflammatory cytokines (IL-1β, IL-6, IL-8) but also effectively counteracted the rebound elevation of CCL-20 exacerbated by DEX in the M4-stimulated model. Importantly, the topical application of ART presents a promising therapeutic strategy, particularly due to its potential to mitigate adverse effects associated with glucocorticoid therapies, such as those linked to CCL-20 rebound. Mechanistically, ART exerted these therapeutic effects primarily by inhibiting the phosphorylation of NF-κB p65 and STAT3 in keratinocytes. The findings underscore that ART ameliorates psoriasis-related inflammation and proliferation through modulating the NF-κB and STAT3 signaling pathways. The inflammatory response centered on IL-17A and the abnormal keratinization state are the most critical pathological processes in psoriasis, with the aberrantly expressed CCL-20 and Keratin17 (Krt17) via NF-κB and STAT3 pathways in keratinocytes serving as key molecular targets within these processes. In complementary and alternative medicine (CAM), ART combined with DEX is an ideal choice for anti-inflammatory treatment. In conclusion, the observed synergy between artesunate and glucocorticoids further highlights its potential in combination therapies.