Clematis Tangutica (Maxim.) Korsh. extracts promote melanogenesis via PKA/CREB activation and multi-cytokine inhibition: A novel dual targeting strategy for vitiligo therapy.

Abstract

BACKGROUND: Dysregulation of melanin contributes to pigmentation disorders including vitiligo, which lacks effective and safe therapeutic options. Despite advances in immunomodulatory therapies, current treatments often fail to address both the loss of melanocytes and the underlying autoimmune pathology driving the disease. Clematis tangutica (Maxim.) Korsh. (C. tangutica), a traditional Chinese Tibetan medicine adapted to high-altitude UV stress, remains unexplored in pigment regulation. PURPOSE: This study aimed to assess the effects of C. tangutica leaf and stem extracts (CTLE and CTSE) on melanogenesis and their potential roles in vitiligo, as well as to elucidate the underlying molecular mechanisms. METHODS: The melanogenic effects of CTLE and CTSE were evaluated in B16F10 melanoma cells, zebrafish and a monobenzone-induced vitiligo mouse model. Label-free quantitative proteomics, immunoblotting and immunofluorescence analyses were performed to identify the underlying signaling pathways. RESULTS: Both CTLE and CTSE significantly enhanced melanogenesis in vitro and in zebrafish. In the vitiligo mouse model, CTSE induced robust repigmentation and reduced pro-inflammatory cytokines, indicating dual melanogenic and immunomodulatory activity. Both extracts upregulated MITF and TYR expression. Proteomic analysis revealed enrichment of the cAMP/PKA/CREB signaling pathway, with increased CREB phosphorylation confirmed by immunoblotting. Pharmacological inhibition of PKA abolished extract-induced melanogenesis, confirming the essential role of cAMP/PKA/CREB signaling. CONCLUSION: C. tangutica extract promotes melanogenesis via PKA/CREB activation and uniquely exhibits immunomodulatory activity in a vitiligo model. This study provides the first mechanistic evidence for the dual-targeting potential of C. tangutica, as a natural candidate for vitiligo therapy. Our findings highlight a novel phytotherapeutic strategy pigmentary disorders.