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.