DKK1-Mediated Inhibition of Melasma via activating the MITF/tyrosinase Regulation of Oxidative Stress in Melanocytes

Melasma is a common acquired hyperpigmentary disorder characterized by symmetrical, irregular brown patches on sun-exposed facial areas. Its pathogenesis is closely associated with ultraviolet (UV) exposure, genetic predisposition, and hormonal influences, though the precise mechanisms remain incompletely elucidated. The core pathological feature is the hyperactivation of melanocytes, involving α-MSH/MC1R signaling, MITF-dependent melanogenesis, and dysregulation of the Wnt pathway. In melasma lesions, fibroblasts exhibit upregulated secretion of Wnt agonists and reduced expression of the Wnt inhibitor Dickkopf-1 (DKK1), leading to aberrant activation of the canonical Wnt/β-catenin pathway, which promotes melanocyte proliferation and melanin synthesis. Oxidative stress is another pivotal mechanism, wherein UV-induced reactive oxygen species (ROS) accumulation disrupts the NRF2 antioxidant system, activates inflammatory factors like NF-κB, and exacerbates melanin production and transfer. As a natural inhibitor of the canonical Wnt pathway, DKK1 blocks signal transduction by binding to LRP5/6 receptors. It has been shown to inhibit MITF expression and melanogenesis in melanoma, but its role in melasma is unclear. This study hypothesizes that DKK1 may ameliorate melasma by attenuating ROS-mediated activation of the MITF/tyrosinase axis and melanosome transfer in melanocytes. Combining cell models with clinical sample analysis, the study aims to systematically elucidate the multidimensional mechanisms involving oxidative stress, the inflammatory microenvironment, and melanin synthesis regulation. This work seeks to provide a theoretical basis for developing DKK1-targeted, precise therapeutic strategies for melasma, moving beyond the traditional MITF/tyrosinase research framework and exploring novel intervention avenues.