Altered laminin signaling destinates melanocyte reprogramming in vitiligo

Vitiligo is an autoimmune skin disorder characterized by progressive melanocyte loss, yet its underlying mechanisms remain unclear. Likewise, the specific molecules and mechanisms mediating melanocyte adhesion to the basement membrane (BM) are poorly understood despite their essential role in skin homeostasis. Here, we identify dystroglycan-laminin-211 as the primary adhesion mechanism anchoring melanocytes to the BM in normal skin. In vitiligo, this adhesion shifts to integrin α3β1-laminin-332 binding. This transition activates the Hippo and MAPK pathways via Rho-F-actin signaling, inducing c-JUN-mediated dedifferentiation and neural crest-like reprogramming. Dedifferentiated melanocytes lose their epidermal identity, acquire multi-lineage potential, and resist repigmentation. Pharmacological inhibition of this dedifferentiation process restores pigmentation in leukoderma models and skin explants from the patient with vitiligo. Notably, JAK inhibitors directly promote melanocyte differentiation, independent of any immunomodulation. These findings identify melanocyte reprogramming as a central pathogenic mechanism in vitiligo and provide novel therapeutic strategies targeting adhesion and fate for disease intervention.