Objective Liver fibrosis is a prelude to a host of end-stage liver diseases. Hepatic stellate cells (HSCs), switching from a quiescent state to myofibroblasts, are the major source for excessive production of extracellular matrix proteins. In the present study, we investigated the role of Suv39h1, a lysine methyltransferase, in HSC-myofibroblast transition and the implication in liver fibrosis. Design HSC-specific or myofibroblast-specific Suv39h1 deletion was achieved by crossbreeding the Suv39h1 f/f mice to the Lrat -Cre mice or the Postn -CreERT2 mice. Liver fibrosis was induced by CCl4 injection or bile duct ligation. Results We report that Suv39h1 expression was universally upregulated during HSC-myofibroblast transition in different cell and animal models of liver fibrosis and in human cirrhotic liver tissues. Consistently, Suv39h1 knockdown blocked HSC-myofibroblast transition in vitro. HSC-specific or myofibroblast-specific deletion of Suv39h1 ameliorated liver fibrosis in mice. More importantly, Suv39h1 inhibition by a small-molecule compound chaetocin dampened HSC-myofibroblast transition in cell culture and mitigated liver fibrosis in mice. Mechanistically, Suv39h1 bound to the promoter of heme oxygenase 1 (HMOX1) and repressed HMOX1 transcription. HMOX1 depletion blunted the effects of Suv39h1 inhibition on HSC-myofibroblast transition in vitro and liver fibrosis in vivo. Transcriptomic analysis revealed that HMOX1 might contribute to HSC-myofibroblast transition by modulating retinol homeostasis. Finally, myofibroblast-specific HMOX1 overexpression attenuated liver fibrosis in both a preventive scheme and a therapeutic scheme. Conclusions Our data demonstrate a previously unrecognised role for Suv39h1 in liver fibrosis and offer proof-of-concept of its targetability in the intervention of cirrhosis. Data are available upon reasonable request. The data that support the findings of this study are available upon reasonable request.

中文翻译：

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组蛋白甲基转移酶 Suv39h1 调节肝星状细胞活化并可靶向治疗肝纤维化

目的 肝纤维化是多种终末期肝病的前奏。肝星状细胞（HSC）从静止状态转变为肌成纤维细胞，是细胞外基质蛋白过量产生的主要来源。在本研究中，我们研究了 Suv39h1（一种赖氨酸甲基转移酶）在 HSC-肌成纤维细胞转变中的作用及其对肝纤维化的影响。设计 HSC 特异性或肌成纤维细胞特异性 Suv39h1 缺失是通过将 Suv39h1 f/f 小鼠与 Lrat -Cre 小鼠或 Postn -CreERT2 小鼠杂交来实现的。通过注射CCl4或结扎胆管诱导肝纤维化。结果我们报告，在不同细胞和动物肝纤维化模型以及人肝硬化肝组织中，Suv39h1 表达在 HSC 向肌成纤维细胞转化过程中普遍上调。一致的是，Suv39h1 敲低在体外阻断了 HSC 向肌成纤维细胞的转变。 HSC 特异性或肌成纤维细胞特异性删除 Suv39h1 可改善小鼠的肝纤维化。更重要的是，小分子化合物毛壳素抑制 Suv39h1 抑制了细胞培养中的 HSC-肌成纤维细胞转变，并减轻了小鼠的肝纤维化。从机制上讲，Suv39h1 与血红素加氧酶 1 (HMOX1) 的启动子结合并抑制 HMOX1 转录。 HMOX1 耗竭减弱了 Suv39h1 抑制对体外 HSC-肌成纤维细胞转变和体内肝纤维化的影响。转录组分析表明，HMOX1 可能通过调节视黄醇稳态来促进 HSC 向肌成纤维细胞的转变。最后，肌成纤维细胞特异性 HMOX1 过度表达在预防方案和治疗方案中均减轻了肝纤维化。结论 我们的数据证明了 Suv39h1 在肝纤维化中的先前未被认识的作用，并为其干预肝硬化的靶向性提供了概念证明。数据可根据合理要求提供。支持本研究结果的数据可根据合理要求提供。