6′‐O‐Caffeoylarbutin: A Stable and Long‐Lasting Skin‐Lightening Agent Targeting Melanogenesis Through MITF Pathway Modulation

The cosmetic application of arbutin (AR) has recently been challenged due to concerns regarding the skin toxicity associated with its metabolite, hydroquinone (HQ). While the derivatization of AR provides a strategy to promote stability, the multistep and complicated chemical synthesis restricts its industrial production. The present study reported a naturally derived AR derivative, 6′‐O‐caffeoylarbutin (CA), which is hypothesized to resist hydrolysis to HQ owing to the conjugation effect and steric hindrance, resulting in better stability. To verify this hypothesis, the degradation of CA and AR was investigated using high‐performance liquid chromatography with diode‐array detection. The skin‐lightening substances, AR and caffeic acid, were found in the degradation products of CA under acidic conditions, which also contained lower quantities of HQ compared to that generated by AR. However, CA was not degraded under enzymatic conditions, exhibiting better stability, which might contribute to its prolonged efficacy and reduced toxicity. The long‐lasting skin‐lightening efficacy of CA was further verified in a zebrafish drug‐withdrawal model. Notably, Mechanistic investigations revealed that CA disrupts melanosome maturation and trafficking by modulating the melanocyte‐inducing transcription factor‐regulated pathway, providing molecular insights into its skin‐lightening efficacy.