Heat Stress Promotes Fibroblast-Derived WNT5A Secretion Through m⁶A Modification to Activate Melanogenesis

As the impact of global warming continues to intensify, the effects of heat stress on the skin are becoming increasingly evident. Growing clinical evidence suggests that heat stress can induce cutaneous hyperpigmentation. However, the underlying mechanisms remain incompletely understood. In this study, we demonstrate that heat stress promotes repigmentation in vitiligo lesions and induces melanogenesis in depigmented mouse skin. Mechanistically, we reveal that heat stress upregulates WNT5A expression and paracrine secretion in dermal fibroblasts (FB) through METTL3-mediated N⁶-methyladenosine (m⁶A) modification. The stability of WNT5A mRNA is regulated through a YTHDC1-dependent pathway. Treatment with recombinant WNT5A protein significantly increases melanin content in melanocytes (MC), MNT1 cells, and human skin explants. Furthermore, WNT5A induces the expression of both β-catenin and its receptor FZD10 in MC. Functional rescue experiments confirm that FZD10 knockdown abolishes WNT5A- and heat stress-induced β-catenin activation, thereby attenuating melanogenesis. Collectively, our findings elucidate a novel mechanism whereby heat stress triggers fibroblast-derived WNT5A secretion via METTL3/YTHDC1-dependent m⁶A methylation to promote melanogenesis. This study provides novel insights into the pathogenesis of heat-induced skin pigmentation disorders, and reveals the potential of thermotherapy as a promising avenue for treating hypopigmentary diseases.