Glabridin Promotes Melanosome Degradation and Alleviates Melanosome-Induced Mitochondrial Dysfunction in Keratinocytes via Autophagy

Background: The excessive accumulation of melanosomes within keratinocytes contributes to skin hyperpigmentation and disrupts normal epidermal proliferation. Glabridin, an isoflavone derived from Glycyrrhiza glabra L., is a potent skin-lightening agent with tyrosinase-inhibitory activity. This study aims to further elucidate the skin-lightening mechanism of glabridin by investigating its effects on melanosome degradation. Methods: We investigated the effect of glabridin on melanosome degradation by measuring melanin content and PMEL17 protein levels. Autophagy activity was evaluated by mRNA sequencing, Western blot, and immunofluorescence. In vivo depigmenting efficacy was examined using epidermal skin equivalents and zebrafish embryos. Additionally, ATP content and mitochondrial membrane potential were measured to determine whether glabridin ameliorates melanosome-induced mitochondrial dysfunction. Results: Glabridin promoted melanosome degradation in keratinocytes and exhibited depigmenting effects in both pigmented epidermal skin equivalents and zebrafish embryos. Mechanistically, glabridin activated autophagy, and pharmacological inhibition of autophagy blocked its depigmenting effects. Additionally, we found that melanosome accumulation impaired mitochondrial function in keratinocytes, an effect that was reversed by glabridin. Conclusions: These findings demonstrate that glabridin promotes melanosome degradation via autophagy activation, which is associated with improved mitochondrial function, providing mechanistic insight into its skin-lightening effects.