Mechanisms Underlying Treatment Of Psoriasis With Boswellic Acid And Its Derivate

Psoriasis is a chronic,immune-mediated disorder that mainly affects the skin and joints,with an estimated global prevalence of 2-3%.WHO has listed psoriasis as one of the global health issues.Psoriasis is easy to relapse and difficult to cure thoroughly.Natural compounds with bioactivity have been proved to be effective in psoriasis treatment,and also good tools to identify new targets with therapeutic potentials.Tranditional herb frankincense exerts anti-inflammatory and pain-relieving effects,and acetyl-11-keto-?-boswellic acid(AKBA)is the most bioactive ingredient of boswellic acids extracted from frankincense.Our study aims to investigate the effects and mechanisms of AKBA and its derivate SZB-025 in psoriasis treatment.In our study,we performed Imiquimod(IMQ)induced mouse model of psoriasis,and it turned out that topical application of AKBA could alleviate the severity of disease.To explore the targets and molecular mechanism of AKBA,we performed pull-down assay,molecular docking and site-directed mutagenesis study.And we found AKBA can bind to methionine adenosyltransferase 2A(MAT2A)directly at an allosteric site at the interface of MAT2A dimer.AKBA could inhibit enzyme activity of MAT2A,decrease level of S-adenosylmethionine(SAM),reprogram one?carbon metabolism,and affect histone methylation in cells.Also,untargeted metabolomics of epidermis showed that one?carbon metabolism was activated in psoriasis patients,which confirms the therapeutic potential of AKBA.Given that AKBA is a well-known natural compound with determined chemical structure,we modified AKBA with a functional group to be SZB-025.We employed mouse model by systemic delivery to validate the therapeutic effect of SZB-025.SZB-025 could directly interact with glyceraldehyde-3-phosphate dehydrogenase(GAPDH),and inhibit T_H17 differentiation while promote T_reg differentiation via glycolysis reprogramming,and eventually ameliorate the phenotypes of psoriasis mouse.In summary,our study identified MAT2A as novel interacting protein of AKBA and MAT2A can regulate one-carbon metabolism and histone methylation via SAM in keratinocytes.Both AKBA and SZB-025 can relieve psoriasis severity effectively.SZB-025 can inhibit T_H17 differentiation while promote T_reg differenticaiton via GAPDH,one of the key enzymes involved in glycolysis pathway.And these findings provide new therapeutic targets and strategies in psoriasis treatment,and maybe also in other immune diseases.