Discovery of pinoresinol dimethyl ether as a natural PDE4 inhibitor with anti-psoriatic effects.

Psoriasis is a complex chronic inflammatory disease that severely impairs patients' quality of life. However, current medications could only control the symptoms but not cure psoriasis with unmet medical needs. Targeting phosphodiesterase 4 (PDE4) represents a validated therapeutic strategy for psoriasis, though the clinical application of existing PDE4 inhibitors is often hampered by systemic side effects. In this study, we identified pinoresinol dimethyl ether (PDME), a natural furanoid lignan previously reported to be isolated from the stem bark of Magnolia Kobus, as a novel PDE4 inhibitor (IC50 = 0.90 μM) through an integrated virtual screening approach. The binding mode of PDME to PDE4 was clearly elucidated through molecular dynamics simulations, isothermal titration calorimetry, and co-crystal structure analysis, revealing an enthalpy-driven interaction involving key hydrogen bonds with Gln369 and π-π stacking within the hydrophobic clamp. In vitro, PDME significantly suppressed the expression of pro-inflammatory cytokines in keratinocytes. In a murine imiquimod-induced psoriasis model, PDME treatment markedly alleviated psoriatic lesions, reduced skin thickening, and suppressed inflammatory responses. These findings highlight PDME as a promising natural PDE4 inhibitor with significant potential for the treatment of psoriasis.