Excessive exposure to UVB induces skin diseases.Silibinin,a flavonolignan used for treating liver diseases,is found to be effective against UVB-caused skin epidermal and dermal cell damage.In this study we investigated the molecular mechanisms underlying.Human nonmalignant immortalized keratinocyte HaCaT cells and neonatal human foreskin fibroblasts HFFs were exposed to UVB irradiation.We showed that pre-treatment with silibinin dose-dependently decreased UVB-induced apoptosis of HaCaT cells.Furthermore,we showed that silibinin treatment inhibited nuclear translocation of YAP after UVB irradiation.Molecular docking analysis and DARTS assay confirmed the direct interaction of silibinin with YAP.Silencing YAP by siRNA had no influence on the survival of HaCaT cells,whereas inhibiting classical YAP-TEAD signaling pathway by siRNA targeting TEAD1 or its pharmaceutical inhibitor verteporfin further augmented UVB-induced apoptosis,suggesting that YAP-TEAD pathway was prosurvival,which did not participate in the protective effect of silibinin.We then explored the pro-apoptotic YAP-p73 pathway.p73 was upregulated in UVB-irradiated cells,but reduced by silibinin cotreatment.The mRNA and protein levels of p73 target genes(PML,p21 and Bax)were all increased by UVB but decreased by silibinin co-treatment.Inhibiting p73 by using siRNA reduced UVB-induced apoptosis,suggesting that downregulation of p73 was responsible for the cytoprotective effect of silibinin.In HFFs,the upregulated YAP-p73 pathway by UVB irradiation was also suppressed by silibinin.Collectively,YAP-p73 pathway is a major cause of the death of UVB-exposed epidermal HaCaT cells and dermal HFFs.Silibinin directly inhibits YAP-p73 pathway,exerting the protective action on UVB-irradiated skin cells.

Wei-wei Liu;Fang Wang;Can Li;Xiao-yu Song;Wuxiyar Otkur;Yu-ying Zhu;Toshihiko Hayashi;Kazunori Mizuno;Shunji Hattori;Hitomi Fujisaki;Takashi Ikejima

Wuya College of Innovation,Shenyang Pharmaceutical University,Shenyang 110016,China;CAS Key Laboratory of Separation Science for Analytical Chemistry,Dalian Institute of Chemical Physics,Chinese Academy of Sciences,Dalian 116023,China;Department of Chemistry and Life science,School of Advanced Engineering,Kogakuin University,2665-1,Nakanomachi,Hachioji,Tokyo 192-0015,Japan;Nippi Research Institute of Biomatrix,Toride,Ibaraki 302-0017,Japan;Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research&Development,Shenyang 110016,China

中国药理学报（英文版）

[1]Wei-wei Liu;Fang Wang;Can Li;Xiao-yu Song;Wuxiyar Otkur;Yu-ying Zhu;Toshihiko Hayashi;Kazunori Mizuno;Shunji Hattori;Hitomi Fujisaki;Takashi Ikejima-.Silibinin relieves UVB-induced apoptosis of human skin cells by inhibiting the YAP-p73 pathway)[J].中国药理学报（英文版）,2022(08):2156-2167

Silibinin,p73,flavonolignan,foreskin,HFFs,silibinin,prosurvival,cotreatment,cytoprotective

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