PUBLICATION
Apigenin promotes melanogenesis and melanosome transport through the c-KIT/Raf-1/MAPK/CREB pathway in HEMCs
- Authors
- Lv, J., Meng, D., Zhang, H., Xu, W., An, X., Yin, C., Zou, K., Gao, R.
- ID
- ZDB-PUB-250513-14
- Date
- 2025
- Source
- Frontiers in pharmacology 16: 15728781572878 (Journal)
- Registered Authors
- Keywords
- HEMCs, apigenin, c-KIT/Raf-1/MAPK pathway, melanogenesis, melanosome transport, pigmentation disorders
- MeSH Terms
- none
- PubMed
- 40356959
Citation
Lv, J., Meng, D., Zhang, H., Xu, W., An, X., Yin, C., Zou, K., Gao, R. (2025) Apigenin promotes melanogenesis and melanosome transport through the c-KIT/Raf-1/MAPK/CREB pathway in HEMCs. Frontiers in pharmacology. 16:15728781572878.
Abstract
Introduction Apigenin, a natural flavonoid with well-established antioxidant, anticancer, and anti-inflammatory activities, has recently attracted attention for its pigmentation-promoting effects. However, the underlying molecular mechanisms driving its melanogenic activity remain incompletely understood.
Method To investigate apigenin's effects on melanogenesis, human epidermal melanocytes (HEMCs), zebrafish embryos, and human skin explants were treated with apigenin. Melanin content, dendrite formation, and melanosome maturation were evaluated using spectrophotometry and transmission electron microscopy. Key signaling molecules and proteins involved in melanogenesis and melanosome transport were assessed by Western blotting and immunohistochemistry. The role of the c-KIT receptor was further explored through pharmacological inhibition and genetic knockdown approaches. Functional pigmentation was evaluated by assessing UVB-induced DNA damage markers.
Results Apigenin (10 μM) significantly increased melanin production by 1.8-fold in HEMCs, enhanced dendritic morphology, and promoted stage III-IV melanosome formation. Mechanistically, apigenin induced melanogenesis independently of the MC1R/cAMP/PKA pathway by directly binding to the c-KIT receptor, activating the Raf-1/ERK/RSK cascade, and upregulating MITF. This led to elevated expression of tyrosinase, TRP-1, TRP-2, and melanosome transport proteins Rab27a and Cdc42. Inhibition or knockdown of c-KIT abrogated these effects. In vivo, apigenin restored pigmentation in PTU-induced depigmented zebrafish and increased melanin content by 1.3-fold in human skin explants. Histological analysis confirmed effective melanin transfer to keratinocytes. Additionally, apigenin-treated skin showed reduced UVB-induced DNA damage, indicating enhanced photoprotection.
Discussion These findings demonstrate that apigenin stimulates melanogenesis through a novel c-KIT-dependent signaling pathway and promotes functional pigmentation with photoprotective benefits. Given its dietary origin, favorable safety profile, and multifaceted mechanisms, apigenin holds promise as a therapeutic agent for vitiligo and a natural pigmentation enhancer for dermatological use.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping