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So far, the molecular mechanisms underlying the action of ISX9 still remain elusive.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>To identify a novel agonist of the Wnt\/\u03b2\u2010catenin, a cell\u2010based SuperTOPFlash reporter system was used to screen known\u2010compound libraries. An activation effect of ISX9 on the Wnt\/\u03b2\u2010catenin pathway was analysed with the SuperTOPFlash or SuperFOPFlash reporter system. Effects of ISX9 on Axin1\/LRP6 interaction were examined using a mammalian two\u2010hybrid system, co\u2010immunoprecipitation, microscale thermophoresis, emission spectra and mass spectrometry assays. The expression of Wnt target and stemmness marker genes were evaluated with real\u2010time PCR and immunoblotting. <jats:italic>In vivo<\/jats:italic> hair regeneration abilities of ISX9 were analysed by immunohistochemical staining, real\u2010time PCR and immunoblotting in hair regrowth model using C57BL\/6J mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In this study, ISX9 was identified as a novel agonist of the Wnt\/\u03b2\u2010catenin pathway. ISX9 targeted Axin1 by covalently binding to its N\u2010terminal region and potentiated the LRP6\u2010Axin1 interaction, thereby resulting in the stabilization of \u03b2\u2010catenin and up\u2010regulation of Wnt target genes and stemmness marker genes. Moreover, the topical application of ISX9 markedly promoted hair regrowth in C57BL\/6J mice and induced hair follicle transition from telogen to anagen via enhancing Wnt\/\u03b2\u2010catenin pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Taken together, our study unravelled that ISX9 could activate Wnt\/\u03b2\u2010catenin signalling by potentiating the association between LRP6 and Axin1, and may be a promising therapeutic agent for alopecia treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16046","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T07:39:23Z","timestamp":1675237163000},"page":"1748-1765","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Isoxazole 9 (ISX9), a small molecule targeting Axin, activates Wnt\/\u03b2\u2010catenin signalling and promotes hair 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