Network Pharmacology Approach to Explore the Skin-Lightening Compounds and Potential Mechanisms of Chinese Herbal Medicines.

INTRODUCTION: Herbal formulations have been used for skin whitening in China for centuries, yet systematic evaluations of their efficacy and underlying mechanisms remain limited. This study aims to identify potential anti-melanogenic compounds in traditional skin-whitening herbs using network pharmacology and investigate their mechanisms of action. METHODS: The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen for anti-melanogenic compounds and their potential targets. A protein-protein interaction (PPI) network was constructed using Cytoscape 3.7.2, followed by KEGG pathway enrichment analysis. The pharmacological effects were assessed in a 3D human skin model, and in vitro experiments were conducted to explore the molecular mechanisms of the identified compounds. RESULTS: Eight potential skin-whitening herbs were identified, including Ampelopsis japonica, Nepeta tenuifolia Benth., Scutellaria baicalensis Georgi, Asarum heterotropoides F. Schmidt, Ipomoea nil, Angelica dahurica, Angelica sinensis, and Prunus persica, along with ten active compounds: quercetin, kaempferol, wogonin, beta-sitosterol, baicalein, stigmasterol, anhydroicaritin, agroclavin, moslosooflavone, and acacetin. Among them, quercetin and acacetin demonstrated significant anti-melanogenic effects in the 3D skin model by downregulating ET-1, VEGF, and PTGS2 in keratinocytes. Molecular docking analysis further revealed strong binding affinities of quercetin and acacetin to TLR4, CHUK, and RELA in the NF-κB pathway, suggesting their role in melanogenesis inhibition via suppression of keratinocyte paracrine signaling. CONCLUSIONS: This study highlights the potential of network pharmacology as an effective approach for screening anti-melanogenic compounds from traditional skin-whitening herbs. Quercetin and acacetin were identified as key bioactive compounds that inhibit melanogenesis by modulating keratinocyte signaling pathways.