Ryu Gina, Yoon Eileen Laurel, Kim Wankyu, Jun Dae Won
Department of Life Sciences, College of Natural Science, Ewha Womans University, Seoul 03760, Republic of Korea.
Department of Internal Medicine, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea.
Diagnostics (Basel). 2025 Jan 31;15(3):342. doi: 10.3390/diagnostics15030342.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex metabolic disorder with a diverse spectrum. This study aimed to classify patients with MASLD into molecular subtypes based on the underlying pathophysiology. We performed high-throughput RNA sequencing on 164 liver tissue samples from healthy controls and patients with MASLD. The clustering was based on individual genes or pathways that showed high variation across the samples. Second, the clustering was based on single-sample gene set enrichment analysis. Optimal homogeneity was achieved by dividing the samples into four clusters (one healthy control and three MASLD clusters I-III) based on the top genes or pathways with differences across the samples. No significant differences were observed in waist circumference, blood pressure, glucose, alanine transaminase (ALT), or aspartate transferase (AST) levels between cluster I patients with MASLD and the healthy controls. Cluster I showed the clinical features of lean MASLD. Cluster III of MASLD demonstrated hypertension and a T2DM prevalence of 57.1% and 50.0%, respectively, with a significantly higher fibrosis burden (stage of fibrosis, liver stiffness, and FIB-4 value) than clusters I and II. Cluster III was associated with severe fibrosis and abnormal glucose homeostasis. In MASLD cluster I, the sphingolipid and GPCR pathways were upregulated, whereas the complement and phagocytosis pathways were downregulated. In MASLD cluster II, the cell cycle and NOTCH3 pathways increased, whereas the PI3K and insulin-related pathways decreased. In MASLD cluster III, increased activity occurred in the interleukin-2 and -4 and extracellular matrix pathways, coupled with decreased activity in the serotonin 2A and B pathways. MASLD can be divided into three distinct molecular phenotypes, wherein each is characterized by a specific molecular pathway.
代谢功能障碍相关脂肪性肝病（MASLD）是一种具有多种表现的复杂代谢紊乱疾病。本研究旨在根据潜在的病理生理学将MASLD患者分类为分子亚型。我们对164份来自健康对照者和MASLD患者的肝组织样本进行了高通量RNA测序。聚类基于在样本间显示出高度变异的单个基因或通路。其次，聚类基于单样本基因集富集分析。通过根据样本间差异最大的顶级基因或通路将样本分为四个聚类（一个健康对照聚类和三个MASLD聚类I - III），实现了最佳的同质性。MASLD聚类I患者与健康对照者在腰围、血压、血糖、丙氨酸转氨酶（ALT）或天冬氨酸转氨酶（AST）水平上未观察到显著差异。聚类I表现出瘦型MASLD的临床特征。MASLD聚类III分别显示高血压患病率为57.1%，2型糖尿病患病率为50.0%，其纤维化负担（纤维化分期、肝脏硬度和FIB - 4值）显著高于聚类I和II。聚类III与严重纤维化和异常葡萄糖稳态相关。在MASLD聚类I中，鞘脂和GPCR通路上调，而补体和吞噬作用通路下调。在MASLD聚类II中，细胞周期和NOTCH3通路增加，而PI3K和胰岛素相关通路减少。在MASLD聚类III中，白细胞介素 - 2和 - 4以及细胞外基质通路活性增加，同时血清素2A和B通路活性降低。MASLD可分为三种不同的分子表型，其中每种表型都具有特定的分子通路特征。
