非酒精性脂肪性肝病（NAFLD）是一种多因素病症，其病因复杂。随着肥胖症的流行，全球的发病率不断增加，现在被认为是西方国家最常见的肝病。NAFLD的发展和进展机制非常复杂，尚不完全理解。越来越多的研究显示，表观遗传和表观转录组机制的紊乱在多种疾病，包括慢性肝病中起到了致病的作用。本研究对合计903例肝组织样本进行了表观遗传和表观转录组基因表达的综合分析，这些样本分别对应于正常肝脏患者、肥胖患者以及非酒精性脂肪肝（NAFL）和非酒精性脂肪性肝炎（NASH）患者，这些是NAFLD进展的不同阶段。我们以无偏的方式整合了十个转录组数据集，对它们进行了强有力的分析和比较。我们描述了这种疾病过程中表观遗传和表观转录组基因表达的完整情况，发现了与疾病进展、尤其是肝纤维化发展密切相关的基因表达异常特征。其中大部分表观遗传和表观转录组效应因子在人类NAFLD中尚未被描述过，其异常表达可能具有致病意义。我们还对参与表观遗传和表观转录组效应因子底物和辅酶代谢的酶的表达进行了综合分析。本研究提供了关于NAFLD病因的新信息，并可能在指导治疗该病以及其进展到肝细胞癌阶段的药物靶点鉴定方面发挥作用。© 2023. 作者（们）。

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition with a complex etiology. Its incidence is increasing globally in parallel with the obesity epidemic, and it is now considered the most common liver disease in Western countries. The precise mechanisms underlying the development and progression of NAFLD are complex and still poorly understood. The dysregulation of epigenetic and epitranscriptomic mechanisms is increasingly recognized to play pathogenic roles in multiple conditions, including chronic liver diseases. Here, we have performed a comprehensive analysis of the expression of epigenetic and epitranscriptomic genes in a total of 903 liver tissue samples corresponding to patients with normal liver, obese patients, and patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), advancing stages in NAFLD progression. We integrated ten transcriptomic datasets in an unbiased manner, enabling their robust analysis and comparison. We describe the complete landscape of epigenetic and epitranscriptomic genes' expression along the course of the disease. We identify signatures of genes significantly dysregulated in association with disease progression, particularly with liver fibrosis development. Most of these epigenetic and epitranscriptomic effectors have not been previously described in human NAFLD, and their altered expression may have pathogenic implications. We also performed a comprehensive analysis of the expression of enzymes involved in the metabolism of the substrates and cofactors of epigenetic and epitranscriptomic effectors. This study provides novel information on NAFLD pathogenesis and may also guide the identification of drug targets to treat this condition and its progression towards hepatocellular carcinoma.© 2023. The Author(s).