Topical VX-509 Attenuates Psoriatic Inflammation Through the STAT3/FABP5 Pathway in Keratinocytes

Background: The mild or moderate of psoriasis is the main type of patients in hospital, and topical application remains the preferred treatment option for psoriasis therapy, therefore, the development of novel topical agents has an essential role in psoriasis therapy. Objective: To identify the molecular mechanism of VX-509 in psoriasis.Methods: We performed drug screening by IMQ-induced psoriatic like inflammation in mouse model, followed mouse epidermis by RNA-seq to find the key molecules affecting the drug, and verified the expression of key molecules by IHC. We also performed qRT-PCR, WB and Chip experiments by IL-22-induced psoriasis-like cell phenotype.Results: In this study, we identified Decernotinib (VX-509), which topical application significantly attenuated IMQ-induced psoriatic like inflammation in mouse model. And then, we verified FABP5 was significantly decreased in VX-509 treated mouse epidermis by RNA-seq. FABP5 is a key molecule in lipid metabolism, administration of FABP5 inhibitor or knock down of FABP5 expression remarkably abrogated psoriatic inflammation as well as lipid metabolism. Mechanistically, our finding showed that VX-509 blocked the IL-22 ligand bound to its receptor, as a consequence, this compound suppressed IL-22 induced pathway, particular in phosphorylation of Stat3. Furthermore, we identified Stat3 is a transcriptional factor associated with FABP5 promoters and VX-509 treatment remarkably attenuated IL-22-induced FABP5 expression through Stat3 activation in Keratinocytes.Conclusions: This study demonstrated administration of VX-509 is a potential promising topical drug for treatment of psoriasis, FABP5 is a novel targeted molecule in psoriasis therapy.Funding Information: This work was supported by National Key Research and Development Program of China (2020YFA0112904), Grant No. 82073458, 81830096, 81974476, 82173424 by National Natural Science, The science and technology innovation Program of Hunan Province(2021RC4013), the Program of Introducing Talents of Discipline to Universities (111 Project, No. B20017). Declaration of Interests: The authors declare no conflicts of interest.Ethics Approval Statement: Approved by the local ethical institutional review board (Xiangya Hospital, Central South University, IRB-20180311).