He Jinyong, Xiao Cuicui, Li Cuiping, Yang Fan, Du Cong
Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Liver Res. 2023 Jun 16;7(2):145-155. doi: 10.1016/j.livres.2023.06.001. eCollection 2023 Jun.
Metabolic dysfunction-associated fatty liver disease (MAFLD) is now the most prevalent chronic liver disease worldwide, with an increasing incidence rate. MAFLD is a heterogeneous disease that can have a low or high-risk profile for developing severe liver disease in its natural course. Recent evidence has highlighted the critical role of RNA methylation modification in the pathogenesis of various liver diseases. However, it remains unclear whether the RNA N1-methyladenosine (mA) modification of immune cells could potentially contribute to the pathogenesis and heterogeneity of MAFLD.
To address this issue, we conducted an integrated bioinformatics analysis of MAFLD bulk and single-cell RNA sequencing (scRNA-seq) data to pinpoint mA regulators in the network. This was followed by a description of the immune landscape, pathway enrichment analysis, and molecular subtyping.
The expression patterns of mA regulatory genes stratify MAFLD into two molecular subtypes, Cluster 1 and Cluster 2. These subtypes demonstrate different immune cell infiltration with distinct inflammation characteristics, which suggest different immune-inflammatory responses in the liver. Notably, Cluster 2 is associated with pro-inflammation and may be more likely to lead to progressive stages of MAFLD. Through intersection analysis of weighted gene co-expression network analysis (WGCNA) and mA regulatory genes, three true hub genes (, , and ) were identified, all of which were strongly correlated with infiltrating immune cells. The specific signaling pathways involved in the three core genes were derived from genomic variation analysis. Furthermore, scRNA-seq data from 33,168 cells from six liver samples identified 26 cell clusters and eight cell types, with endothelial cells, macrophages, and monocytes showing the most significant differences between MAFLD and normal controls. The cell-cell communication network between immune cells and non-parenchymal cells was extremely sophisticated and changed significantly in MAFLD.
In summary, these findings demonstrate the involvement of mA in MAFLD heterogeneity and emphasize the crucial role of mA modulation of immune cells in regulating inflammation in MAFLD. These results may suggest potential therapeutic strategies for MAFLD.
代谢功能障碍相关脂肪性肝病（MAFLD）是目前全球最普遍的慢性肝病，发病率不断上升。MAFLD是一种异质性疾病，在其自然病程中发生严重肝病的风险可能较低或较高。最近的证据强调了RNA甲基化修饰在各种肝病发病机制中的关键作用。然而，免疫细胞的RNA N1-甲基腺苷（mA）修饰是否可能导致MAFLD的发病机制和异质性仍不清楚。
为了解决这个问题，我们对MAFLD批量和单细胞RNA测序（scRNA-seq）数据进行了综合生物信息学分析，以确定网络中的mA调节因子。随后描述了免疫格局、通路富集分析和分子亚型。
mA调节基因的表达模式将MAFLD分为两种分子亚型，即Cluster 1和Cluster 2。这些亚型表现出不同的免疫细胞浸润，具有不同的炎症特征，这表明肝脏中存在不同的免疫炎症反应。值得注意的是，Cluster 2与促炎相关，可能更有可能导致MAFLD的进展阶段。通过加权基因共表达网络分析（WGCNA）和mA调节基因的交叉分析，确定了三个真正的枢纽基因（、和），所有这些基因都与浸润免疫细胞密切相关。这三个核心基因涉及的特定信号通路来自基因组变异分析。此外，来自六个肝脏样本的33168个细胞的scRNA-seq数据确定了26个细胞簇和八种细胞类型，其中内皮细胞、巨噬细胞和单核细胞在MAFLD和正常对照之间表现出最显著的差异。免疫细胞与非实质细胞之间的细胞间通讯网络极其复杂，在MAFLD中发生了显著变化。
总之，这些发现证明了mA参与MAFLD异质性，并强调了mA调节免疫细胞在调节MAFLD炎症中的关键作用。这些结果可能为MAFLD提示潜在的治疗策略。
