Baeckea frutescens Suppresses Melanogenesis via Modulation of PKA/CREB and ERK/MAPK Pathways: Insights from Cellular, Zebrafish, and In Silico Analyses

Background: Baeckea frutescens L. (BF) has been reported as a potential natural source for skin-whitening agents. However, its antimelanogenic activity and mechanisms remain unclear. Methods: The antimelanogenic effects of BF were evaluated in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16F10 cells and in zebrafish embryos. Cell viability, intracellular tyrosinase activity and melanin content were measured. Western blot (WB) analysis was used to examine melanogenesis-related proteins. Network pharmacology and molecular docking were performed to predict potential targets and interactions of BF-derived metabolites. Results: The ethanolic extract of BF reduced intracellular tyrosinase activity and melanin content in cells without cytotoxicity. Western blot analysis showed decreased expression of microphthalmia-associated transcription factor (MITF) and its downstream melanogenic enzymes, including tyrosinase (TYR), tyrosinase-related protein-1 (TRP-1), and dopachrome tautomerase (DCT). In addition, BF reduced phosphorylation of protein kinase A (PKA), cAMP responsive element-binding protein (CREB) and extracellular signal-regulated kinase (ERK), suggesting potential suppression of PKA/CREB and ERK signaling pathways. These regulatory effects may contribute to MITF downregulation and subsequent inhibition of melanogenesis. BF reduced melanin accumulation in zebrafish embryos. Network pharmacology and molecular docking analyses further suggested that BF-derived metabolites, particularly bayogenin, may interact with multiple melanogenesis-related targets. Conclusions: BF may inhibit melanogenesis through coordinated modulation of multiple signaling pathways and may represent a promising skin-whitening candidate.