Multiple gene-drug prediction tool reveals Rosiglitazone based treatment pathway for non-segmental vitiligo

Sijia Zhao; Xi Chen; Kuheli Dutta; Jia Chen; Juan Wang; Qian Zhang; Hong Jia; Jianfang Sun; Yongxian Lai

doi:10.1007/s10753-023-01937-9

Multiple gene-drug prediction tool reveals Rosiglitazone based treatment pathway for non-segmental vitiligo

Inflammation. 2023 Dec 30. doi: 10.1007/s10753-023-01937-9. Online ahead of print.

Authors

Sijia Zhao¹, Xi Chen², Kuheli Dutta², Jia Chen¹, Juan Wang³, Qian Zhang⁴, Hong Jia⁴, Jianfang Sun⁵, Yongxian Lai⁶

Affiliations

¹ Department of dermatologic Surgery, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China.
² Department of Dermatology, Allergology and Venereology, Universitätsklinikum Schleswig-Holstein, Lübeck, Schleswig-Holstein, Germany.
³ School of Medicine, Shanghai University, Shanghai, China.
⁴ Department of Pathology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, People's Republic of China.
⁵ Department of Pathology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, People's Republic of China. JianfangSunPUMC@outlook.com.
⁶ Department of dermatologic Surgery, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China. laiyx@shskin.com.

PMID: 38159176
DOI: 10.1007/s10753-023-01937-9

Abstract

Vitiligo is a skin disease characterized by selective loss of melanocytes, which seriously affects the appearance and causes great psychological stress to patients. 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 "PPAR signaling pathway", "tyrosine metabolism", "nonalcoholic fatty liver disease (NAFLD) pathway", "melanogenesis", and "IL-17 signaling pathway". 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-γ agonist rosiglitazone may promote melanin synthesis via EDNRB. Next, we investigated the mechanism of rosiglitazone and PPAR-γ pathway in promoting melanin production. Consistent with the results of bioinformatics analysis, the expression levels of PPAR-γ, 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-γ and upregulating TYR, TYRP-1, and TYRP-2. Conversely, treatment of melanocytes with the PPAR-γ 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-γ 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.

Keywords: PPAR pathway; bioinformatics analysis; melanogenesis; non-segmental vitiligo; rosiglitazone.