The primary objective of this proposal is to validate the critical role of the mTOR and secondary signaling in skin inflammation with emphasis on psoriasis pathogenesis and to test fisetin, a common natural dietary ingredient for its management. Psoriasis is a chronic and currently incurable inflammatory skin disease that affects an estimated 3% of the world population3, 4,5 with > 8 million afflicted individuals in the US alone3, 4. Psoriasis etiology is incompletely understood, but involves disruption of multiple cell systems impinging on the dynamic interaction amid immune cells and the skin, featuring epidermal hyperplasia, immune cell infiltration, immune-mediators orchestration and skin barrier dysfunction3, 4. The past several decades have recorded a skyrocketing increase in new psoriasis cases, associated with significant decline in patients’ quality of life and an increased risk of arthritis and cardiovascular diseases6. Being multifactorial, curative treatments for mild/moderate psoriasis have proved frustrating and still remain elusive, thus it is unlikely that hitting a single target will effectively control the disease. Thus, there remains a dire need to develop novel and effective mechanisms and target-based strategies for long-term patient benefits. Our preliminary data suggest that amongst multiple signaling networks implicated in psoriasis, the phospho-inositol- 3 Kinase (PI3K)/protein kinase B(Akt)/mammalian target of Rapamycin (mTOR) and MAPK pathways, which regulate cell growth and angiogenesis, are clinically relevant targets that cooperatively promote psoriasis7, 8. We observed that PI3K/Akt/mTOR signaling is hyperactivated in both human psoriatic and imiquimod (IMQ)-induced murine psoriasis-like skin lesions compared to unaffected tissues7, 8. Likewise, our pilot studies on competitive binding, Kd’s and in-silico docking analyses identified fisetin as a potent dual mTOR kinase inhibitor that physically interacts and competitively binds mTOR and p70S6K1 with binding energies of -7 to -10.5Kcal/mol9. In addition, fisetin alone or in combination with activating agents, induced differentiation in normal human epidermal keratinocytes (NHEKs) and inhibited 1) NHEK proliferation, 2) PI3K/Akt/mTOR activation, 3) mTOR activity, 4) secretion of pro-inflammatory cytokines by NHEKs, peripheral blood mononuclear cells (PBMCs) and a CD4+T activated 3 dimensional (3D) Full-Thickness Reconstituted Human Skin equivalent model of Psoriasis (FTRHSP). Based on these observations, we posit that “PI3K/Akt/mTOR and MAPK networks are critical in psoriasis pathogenesis and, fisetin will inhibit the activation of these pathways, suppress proliferation, inflammation and neo-vascularization, and concomitantly induce differentiation to efficiently alleviate psoriasiform disease”.