591 Dual targeting mTOR and autophagy by fisetin alleviates psoriasis-like responses induced by TNF-α and IL-17A in vitro and imiquimod-induced dermatitis in vivo

Recently, the central mTOR pathway has emerged as a clinically relevant player in pathogenesis of psoriasis. Our previous study shown that fisetin, dietary polyphenol, possesses prodifferentiation and inhibitory properties, suppresses psoriasis-like responses vitro. However, effects fisetin on psoriasis vivo underlying mechanisms are unclear. Here, we evaluated fisetin's cytokines(IL-6/22 TNF-A/IL-17A) anti-CD3/CD28 stimulated keratinocytes(HEKa) CD4+T cells compared to rapamycin, known inhibitor mTOR. We observed rapamycin alone or in-combination inhibited(p<0.001) activity HEKa secretion IL-17A IFN-γ co-cultured with HEKa, increased levels autophagy markers LC3A/B Atg5. RNA-Seq analysis, identified 12713 differentially expressed genes(DEGs) fisetin-treated(p<0.0001) 7374 DEGs rapamycin-treated(p<0.001)groups, differently expression patterns PI3K/Akt/mTOR-pathways, psoriasis, epidermal development genes. Using kinase assay silico molecular modeling, high binding-affinity IL-17A, Rac1, PIK51α, which dysregulated targets. In imiquimod(IMQ)-induced mouse model, topical application fisetin(p<0.001) exhibited better effect than rapamycin(p<0.05) reducing skin inflammatory responses, Akt/mTOR phosphorylation levels, modulating oxidative stress lesions. Overall, our data demonstrate potently inhibits targets, upregulates alleviates IMQ-induced murine disease. findings suggest either an adjuvant existing therapies, great potential for treatment other inflammation.