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 depigmenting agent that inhibits Tyrosinase activity and suppresses melanin transfer. This study aims to further elucidate the depigmenting 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 expression. Autophagy activity was evaluated by mRNA Sequencing, Western blot, and immunofluorescence. Depigmenting efficacy was examined using epidermal skin equivalents and zebrafish embryos. 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.

Conclusion: Glabridin promotes melanosome degradation via Autophagy activation, which is associated with improved mitochondrial function. These findings expand its depigmenting mechanisms beyond Tyrosinase inhibition and melanin transfer, supporting its development as a multi-targeted agent for hyperpigmentation.