Dimethyl fumarate ameliorates imiquimod-induced psoriasiform inflammation and suppresses melanogenesis

Psoriasis is a chronic immune-mediated inflammatory disease characterized by IL-23/Th17 axis dysregulation. Dimethyl fumarate (DMF), an oral small-molecule fumaric acid ester as a NF-κB suppressor, is approved for the treatment of multiple sclerosis and psoriasis. However, oral DMF is frequently limited by gastrointestinal adverse effects reported, underscoring the necessity of investigating topical DMF. First, we performed a retrospective chart review and oral DMF was associated with significant improvement in PASI and BSA in patients with mild-to-moderate plaque psoriasis. Therefore, we evaluated the efficacy of DMF administered topically in a 4-day imiquimod-induced psoriasiform mouse model compared to intraperitoneal administration, finding that both routes comparably and significantly reduced clinical severity, inflammatory cell infiltration, and epidermal hyperplasia. Mechanistically, DMF suppressed the mRNA expression of TNF-α, IL-17 C, and S100 families induced by M5 or IL-36γ stimulation in human keratinocytes. STAT3 phosphorylation as well as NF-κB p65 phosphorylation was significantly reduced. In contrast to most anti-psoriasis medications that aggravate hyperpigmentation, DMF reduced melanin content and tyrosinase activity in mouse melanocytes. Furthermore, DMF attenuated UVB-induced melanogenesis in an ex vivo human skin model, accompanied by the suppression of MITF and tyrosinase expression. In conclusion, DMF exerts anti-melanogenic effects in addition to its anti-inflammatory effects. In a short-term, preventive-application mouse model, topical DMF reduced psoriasiform inflammation to an extent comparable to systemic DMF, supporting further investigation of topical DMF as a candidate strategy for psoriasis and associated hyperpigmentation.