Oral and topical formulated fisetin ameliorates psoriasis-like responses in vivo in imiquimod-induced dermatitis in mice

Summary: Abstract Body: Conventional psoriasis treatments are effective but often have severe side effects and reduced efficacy, highlighting the need for safer, cost-effective alternatives. We previously demonstrated that fisetin, a dietary flavonol, has mTOR-inhibitory and anti-inflammatory properties, promotes keratinocyte differentiation, and suppresses psoriasis-like responses in vitro. However, its in vivo efficacy and mechanisms remain unclear. In this study, we evaluated fisetin’s effects, delivered topically and orally, on cytokine expression (TNF-α, IL-17), T-lymphocyte activation, and psoriasis features in imiquimod-induced mouse model, compared to rapamycin, a known mTOR inhibitor. Both fisetin formulations significantly reduced psoriasis hallmarks – epidermal hyperplasia, erythema, scaling, and splenomegaly – while inhibiting mTOR activity (p<0.001), decreasing cytokine expression, and reducing T-lymphocyte activation. RNA-seq revealed 557 differentially expressed genes (DEGs) in fisetin-treated groups (245 upregulated, 312 downregulated) p<0.05, compared to 1,312 DEGs in rapamycin-treated groups, with notable effects on IL-17 signaling, keratinocyte cornification (Loricrin, LCE3C), and cytokine-mediated mTOR activation (CXCL13, HLA-B). Topical fisetin showed superior efficacy, enhancing keratinocyte autophagy via LC3A/B nuclear translocation, absent with systemic (oral) delivery. It also normalized keratin-14 and CD11c+ dendritic cells, suppressed TNF-α production, and inhibited T-lymphocyte activation and STAT3 signaling. Transcriptomic analysis highlighted fisetin’s affinity for IL-17A, Calmodulin-4 and mTOR pathway components, supporting its multitargeted therapeutic potential. Our findings suggest fisetin as a potent nutraceutical capable of alleviating psoriasis by inhibiting mTOR signaling, reducing inflammation, and promoting autophagy. Fisetin shows promise as a standalone or adjunctive therapy for psoriasis. Tolulope O. Omolekan¹, Tithi Roy¹, Konstantin Kousoulas¹, O Dauvergne², JC Chamcheu¹ 1. Pathobiological Sci Department, Louisiana State University, Baton Rouge, LA, United States. 2. Biological Sci and Chem Department, Southern University and A&M College, Baton Rouge, LA, United States. Translational Studies: Preclinical