Hyperpigmentation disorders causing emotional distress require the topical use of
depigmenting agents of natural origin. In this study, the anti-melanogenic effects of the Lilium lancifolium root extract (LRE) were investigated in B16F10 cells. Consequently, a non-cytotoxic concentration of the extract reduced intracellular
melanin content and
tyrosinase activity in a dose-dependent manner, correlating with the diminished expression of core melanogenic
enzymes within cells. LRE treatment also inhibited cyclic
adenosine monophosphate (
cAMP) response element-binding protein (CREB)/
microphthalmia-associated transcription factor signaling, which regulates the expression of
tyrosinase-related genes. Upon examining these findings from a molecular mechanism perspective, LRE treatment suppressed the phosphorylation of
protein kinase A (PKA), p38, and extracellular signal-related
kinase (ERK), which are upstream regulators of CREB. In addition,
L-phenylalanine and regaloside A, specifically identified within the LRE using liquid chromatography-mass spectrometry, exhibited inhibitory effects on
melanin production. Collectively, these results imply that LRE potentially suppresses cAMP-mediated melanogenesis by downregulating PKA/CREB and
mitogen-activated protein kinase (MAPK)/CREB signaling pathways. Therefore, it can be employed as a novel therapeutic ingredient of natural origin to ameliorate
hyperpigmentation disorders.