Bairesi Pills ameliorates vitiligo-like depigmentation by reducing hippuric acid accumulation and regulating MAPK14/β-catenin mediated melanogenesis

Bairesi Pills promote repigmentation in hydroquinone-induced vitiligo mice. • Bairesi Pills reduce hippuric acid levels and restore gut-skin axis homeostasis. • Bairesi Pills and their active constituents including piperine and quercitrin, enhance melanogenesis through modulation of the MAPK14/β-catenin pathway. Background Bairesi Pills is a traditional Uyghur medicinal formula prescribed for vitiligo. However, its bioactive constituents and specific pharmacological mechanisms remain to be fully elucidated. Purpose This study aims to elucidate the underlying mechanisms and identify the active constituents of Bairesi Pills in the treatment of vitiligo. Methods A hydroquinone-induced vitiligo mouse model was established to evaluate the effects of Bairesi in vivo. Serum untargeted metabolomics and gut microbiome analyses were integrated to identify key differential metabolites and explore the association between gut dysbiosis and skin depigmentation. In vitro, melanocyte oxidative injury models were established using H₂O₂ or hippuric acid. Transcriptome sequencing was performed to screen differentially expressed genes and related signaling pathways. MAPK14 overexpression and pharmacological inhibition were further used to verify the effects and mechanisms of Bairesi and its active constituents in alleviating hippuric acid-induced oxidative stress. Results In vivo, Bairesi ameliorated oxidative stress and promoted pigment deposition in vitiligo-like mice, which was associated with enhanced intestinal mucus barrier integrity, reshaped gut microbiota, and reduced hippuric acid accumulation. In vitro, H₂O₂ or hippuric acid induced oxidative injury and MAPK activation in melanocytes, whereas Bairesi, piperine, and quercitrin suppressed MAPK14 activation, alleviated oxidative stress, and restored melanin synthesis, but these protective effects were attenuated by MAPK14 overexpression. Conclusion Bairesi Pills ameliorates vitiligo-like depigmentation by reshaping the gut microbiota–metabolite profile, reducing hippuric acid accumulation, and reversing HA-induced oxidative stress through inhibition of MAPK14 phosphorylation. Download: Download high-res image (219KB) Download: Download full-size image