Marliolide derivative induces melanosome degradation via Nrf2/p62-mediated autophagy

Nuclear factor erythroid 2-related factor 2 (Nrf2), which is linked to autophagy regulation and melanogenesis regulation is activated by marliolide. In this study, we investigated the effect of marliolide derivative on melanosome degradation through autophagy pathway. The effect of marliolide derivative on melanosome degradation was investigated in α-melanocyte stimulating hormone (α-MSH)-treated melanocytes, melanosome-incorporated keratinocyte, and ultraviolet (UV)B-exposed HRM-2 mice (melanin-possessing hairless mice). 5-methyl-3-tetradecylidene-dihydro-furan-2-one (DMF02), a marliolide derivative decreased melanin pigmentation by melanosome degradation in α-MSH-treated melanocytes and melanosome-incorporated keratinocytes evidenced by pre-melanosome protein17 (PMEL17) expression, but did not affect melanogenesis-associated proteins. The UVB-induced hyperpigmentation in HRM-2 mice was also reduced by a topical application of DMF02. DMF02 activated Nrf2 and induced autophagy in vivo evidenced by decrease of PMEL17 in LC3-II-expressed areas. DMF02 also induced melanosome degradation via autophagy in vitro and DMF02-induced melanosome degradation was recovered by chloroquine (CQ), which is an inhibitor of autophagy. In addition, Nrf2 silencing by siRNA attenuated the DMF02-induced melanosome degradation via the suppression of p62. DMF02 induced melanosome degradation in melanocytes and keratinocytes by regulating autophagy via Nrf2-p62 activation. Therefore, Nrf2 activator could be a promising therapeutic agent for reducing hyperpigmentation