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In this study, we performed a comprehensive analysis of two vitiligo microarray datasets from the GEO database using bioinformatics tools to identify 297 up-regulated mRNAs and 186 down-regulated mRNAs, revealing important roles for pathways related to melanin synthesis, tyrosine metabolism, and inflammatory factors, such as \u201cPPAR signaling pathway\u201d, \u201ctyrosine metabolism\u201d, \u201cnonalcoholic fatty liver disease (NAFLD) pathway\u201d, \u201cmelanogenesis\u201d, and \u201cIL-17 signaling pathway\u201d. Combining the Search Tool for Interacting Chemicals (STITCH) database 5.0 and the drug-gene interaction database 3.0 (DGIdb), we identified that the PPAR-\u03b3 agonist rosiglitazone may promote melanin synthesis via EDNRB. Next, we investigated the mechanism of rosiglitazone and PPAR-\u03b3 pathway in promoting melanin production. Consistent with the results of bioinformatics analysis, the expression levels of PPAR-\u03b3, EDNRB, and TYR were significantly reduced in human non-segmental vitiligo skin along with the reduction of MITF, a key gene for epidermal melanogenesis. Meanwhile, rosiglitazone increased melanin synthesis capacity in melanocytes and zebrafish by activating PPAR-\u03b3 and upregulating TYR, TYRP-1, and TYRP-2. Conversely, treatment of melanocytes with the PPAR-\u03b3 antagonist GW resulted in inhibition of melanin synthesis and expression of melanin-related factors. At the same time, simultaneous treatment of rosiglitazone with GW reversed the inhibitory effect of GW on melanin synthesis. In this study, we identified that rosiglitazone, an important insulin sensitizer, promotes melanin synthesis in melanocytes by increasing PPAR-\u03b3 activity and upregulating the expression levels of EDNRB and TYR. These findings may provide new ideas for exploring the pathogenesis and potential therapeutic targets of non-segmental vitiligo.<\/jats:p>","DOI":"10.1007\/s10753-023-01937-9","type":"journal-article","created":{"date-parts":[[2023,12,30]],"date-time":"2023-12-30T11:01:50Z","timestamp":1703934110000},"page":"678-695","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Multiple gene-drug prediction tool reveals Rosiglitazone based treatment pathway for non-segmental vitiligo"],"prefix":"10.1007","volume":"47","author":[{"given":"Sijia","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuheli","family":"Dutta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongxian","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,12,30]]},"reference":[{"issue":"6","key":"1937_CR1","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1159\/000506103","volume":"236","author":"C Bergqvist","year":"2020","unstructured":"Bergqvist, C., and K. 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