The anti-fibrotic drug pirfenidone inhibits liver fibrosis by targeting the small oxidoreductase glutaredoxin-1.
The anti-fibrotic drug pirfenidone inhibits liver fibrosis by targeting the small oxidoreductase glutaredoxin-1.
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DOI：
10.1126/sciadv.abg9241
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发表时间：
2021-09-03
期刊：
影响因子：
13.6
通讯作者：
Xie W
中科院分区：
文献类型：
--
作者：
Xi Y;Li Y;Xu P;Li S;Liu Z;Tung HC;Cai X;Wang J;Huang H;Wang M;Xu M;Ren S;Li S;Zhang M;Lee YJ;Huang L;Yang D;He J;Huang Z;Xie W
吡非尼酮通过靶向谷氧还蛋白-1和减少Smad3谷胱甘肽基化来抑制HSC的激活和肝纤维化。肝星状细胞(HSCs)的激活是肝纤维化的关键致病事件。半胱氨酸残基的蛋白质S谷胱甘肽基化是一种改变蛋白质结构和功能的独特形式的氧化反应。谷氧还蛋白-1(GLRX)通过释放谷胱甘肽(GSH)逆转PSSG。在这项研究中，我们证明了吡非尼酮(PFD)，一种抗肺纤维化药物，以GLRX依赖的方式抑制HSC激活和肝纤维化。Glrx耗竭加重肝纤维化，肝纤维化小鼠和人肝组织GLRx降低，PSSG升高。相反，过表达GLRX可抑制PSSG和肝纤维化。从机制上讲，GLRX抑制HSC的活化可能是通过Smad3的去谷胱甘肽化，从而抑制Smad3的磷酸化，从而抑制纤维化基因的表达。我们的结果确立了GLRX作为PFD的治疗靶点，并揭示了PSSG在肝纤维化中的重要作用。GLRX/PSSG可作为肝纤维化的生物标志物和治疗靶点。
Pirfenidone inhibits HSC activation and liver fibrosis by targeting glutaredoxin-1 and reducing Smad3 glutathionylation. Activation of the hepatic stellate cells (HSCs) is a key pathogenic event in liver fibrosis. Protein S-glutathionylation (PSSG) of cysteine residues is a distinct form of oxidative response that modifies protein structures and functions. Glutaredoxin-1 (GLRX) reverses PSSG by liberating glutathione (GSH). In this study, we showed that pirfenidone (PFD), an anti-lung fibrosis drug, inhibited HSC activation and liver fibrosis in a GLRX-dependent manner. Glrx depletion exacerbated liver fibrosis, and decreased GLRX and increased PSSG were observed in fibrotic mouse and human livers. In contrast, overexpression of GLRX inhibited PSSG and liver fibrosis. Mechanistically, the inhibition of HSC activation by GLRX may have been accounted for by deglutathionylation of Smad3, which inhibits Smad3 phosphorylation, leading to the suppression of fibrogenic gene expression. Our results have established GLRX as the therapeutic target of PFD and uncovered an important role of PSSG in liver fibrosis. GLRX/PSSG can be both a biomarker and a therapeutic target for liver fibrosis.
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影响因子：
4.6
作者：
Komiya C;Tanaka M;Tsuchiya K;Shimazu N;Mori K;Furuke S;Miyachi Y;Shiba K;Yamaguchi S;Ikeda K;Ochi K;Nakabayashi K;Hata KI;Itoh M;Suganami T;Ogawa Y
通讯作者：
Ogawa Y
DOI：
10.3791/56993
发表时间：
2018-02-12
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Cabral F;Miller CM;Kudrna KM;Hass BE;Daubendiek JG;Kellar BM;Harris EN
通讯作者：
Harris EN
影响因子：
10.8
作者：
Hu, Mengying;Zhou, Xuefei;Huang, Leaf
通讯作者：
Huang, Leaf
DOI：
10.1165/rcmb.2010-0249oc
发表时间：
2011-11-01
影响因子：
6.4
作者：
Kuipers, Ine;Guala, Amy S.;Reynaert, Niki L.
通讯作者：
Reynaert, Niki L.
P62/SQSTM1与维生素D受体结合抑制肝星细胞活性，纤维化和肝癌。
影响因子：
50.3
作者：
Duran A;Hernandez ED;Reina-Campos M;Castilla EA;Subramaniam S;Raghunandan S;Roberts LR;Kisseleva T;Karin M;Diaz-Meco MT;Moscat J
通讯作者：
Moscat J