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.

中文翻译：

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抗纤维化药物吡非尼酮通过靶向小氧化还原酶glutaredoxin-1抑制肝纤维化

肝星状细胞 (HSC) 的激活是肝纤维化的关键致病事件。蛋白S半胱氨酸残基的谷胱甘肽化 (PSSG) 是一种独特的氧化反应形式，可改变蛋白质的结构和功能。Glutaredoxin-1 (GLRX) 通过释放谷胱甘肽 (GSH) 来逆转 PSSG。在这项研究中，我们发现吡非尼酮 (PFD) 是一种抗肺纤维化药物，它以 GLRX 依赖性方式抑制 HSC 活化和肝纤维化。Glrx 耗竭加剧了肝纤维化，并且在纤维化小鼠和人类肝脏中观察到 GLRX 减少和 PSSG 增加。相反，GLRX 的过表达抑制了 PSSG 和肝纤维化。从机制上讲，GLRX 对 HSC 活化的抑制可能是由于 Smad3 的脱谷胱甘肽化作用所致，这会抑制 Smad3 磷酸化，从而抑制纤维化基因的表达。我们的研究结果确立了 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 既可以作为肝纤维化的生物标志物，也可以作为治疗靶点。