Abstract
Background and Purpose: Humans have been fighting vitiligo for centuries; however, there remains a lack of efficient therapies. While research has implied the therapeutic potential of Wnt/β -catenin signalling for curing vitiligo, the mechanism underlying this correlation is unclear, and no Wnt-specific anti-vitiligo drug has been reported. Here, we determined a treatment approach for vitiligo that acts through regulation of Wnt and identified two new lead compounds for anti-vitiligo treatment.
Experimental Approach: Wnt agonists were rationally synthesized and evaluated for their effects on vitiligo in B16 cells and C57B/L mice. Furthermore, co-immunoprecipitation and site-directed mutagenesis were employed to determine the mechanism and target of the compounds.
Key Results: HCJA121 and HCJA404 could significantly promote the synthesis of melanin, restore the pigmented function of skin, and improve the symptoms of vitiligo. Mechanistic studies indicated that HCJA121 and HCJA404 target the DAX domain of axin via binding to LYS781 and LEU784, potentiating the axin–LRP6 association and eventually promoting melanogenesis.
Conclusions and Implications: These findings imply an alternative regulatory mechanism of melanogenesis, and the axin protein could be a new target for anti-vitiligo agents, revealing a therapeutic strategy for vitiligo. Besides, HCJA121 and HCJA404 may represent potential candidates for vitiligo treatment.