Psoriasis is a chronic autoinflammatory skin disease lacking curative options. Ronomilast is a novel PDE4i inhibitor with potent anti-inflammatory properties. To evaluate the therapeutic efficacy of topical ronomilast, alone and combined with clobetasol, in an imiquimod (IMQ)-induced psoriasis mouse model. Fifty BALB/c male albino mice were randomly assigned to five groups (n = 10): healthy control, imiquimod-induced, clobetasol-treated (0.05%), ronomilast-treated (0.3%), and combination-treated (ronomilast 0.15% + clobetasol 0.025%). Psoriasis-like lesions were induced by daily topical application of 5% imiquimod for five consecutive days. Treatments were applied topically 3 h after imiquimod. Skin samples were analyzed for IL-17A and IL-23 levels via ELISA, TNF-α expression via immunohistochemistry, and histopathological changes. In silico molecular docking with PDE4B and PDE4D targets was also conducted. Ronomilast significantly reduced IL-17A and IL-23 levels compared to the induction group. The combination therapy produced the greatest reduction in IL-17A and IL-23. TNF-α expression scores were also significantly decreased by ronomilast and the combination relative to the induction group, consistent with histopathological improvements. Molecular docking demonstrated that ronomilast has higher binding affinity than roflumilast for PDE4B and comparable affinity for PDE4D. Topical ronomilast alone or combined with clobetasol, substantially ameliorates psoriasiform dermatitis by inhibiting key inflammatory cytokines. These results strengthen its prospects as an antipsoriatic candidate; nonetheless, more clinical investigations are necessary to validate its effectiveness and safety in humans.
