Curcumol reprograms the psoriatic microenvironment by interrupting the IL-36-NLRP3-NETs inflammatory circuit

Psoriasis, a chronic immune-mediated dermatosis, poses significant therapeutic challenges due to its complex multifactorial pathogenesis. Curcumol, a bioactive sesquiterpenoid derived from Rhizoma Curcumae, demonstrates broad-spectrum pharmacological activities including notable anti-inflammatory and immunomodulatory properties. We first demonstrated that curcumol disrupts the synergistic pro-inflammatory crosstalk between fibroblasts and keratinocytes by suppressing Poly(I:C)/LPS-induced expression of IL-36α, IL-36γ, and NLRP3 inflammasome activation. Using an ex vivo model, we further showed that curcumol interrupts a self-amplifying loop between IL-36γ and the NLRP3 inflammasome. In imiquimod-induced murine psoriasis, curcumol not only ameliorated skin inflammation and restored keratinocyte differentiation but also profoundly reshaped the immune landscape by dual targeting of inflammasome activation and neutrophil NETosis, thereby attenuating the infiltration of neutrophils and macrophages. These findings reveal that curcumol alleviates psoriatic pathology via coordinated modulation of the IL-36γ-NLRP3-NETs inflammatory circuit, highlighting its potential as a novel multi-target therapeutic strategy for psoriasis management.