Zhao Xiaofang, Wang Senyan, Liu Qi, Wei Wenjuan, Sun Xiaoyan, Song Hao, Xu Jing, Zhang Shuijun, Wang Hongyang, Fu Jing
Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepatobiliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical University, Shanghai, China.
Clin Transl Med. 2025 Jan;15(1):e70198. doi: 10.1002/ctm2.70198.
Alcohol-related liver disease (ALD) is a common chronic liver disease caused by long-term excessive alcohol consumption and responsible for more than half of all liver-related deaths worldwide. The molecular mechanisms associated with ALD were not fully understood. In this study, we performed single-cell RNA sequencing on liver tissues obtained from ALD patients and healthy liver donors. We identified an ALBKRT7 epithelial population that expressed both hepatocyte and biliary markers significantly expanded in ALD livers. The ALBKRT7 epithelial cells were demonstrated to have stem cell properties and malignant transformation potentials. Moreover, ALBKRT7 epithelium-derived ALD organoids promote the tumour growth by activating Wnt/β-catenin signalling of liver cancer cells. Most importantly, blocking the Wnt protein secretion or knockdown the Wnt receptor suppressed the tumour promoting effect of ALD organoids. Our study provides important insights that Wnt signalling can be targeted in patients with advanced alcohol-related cirrhosis to prevent malignant transformation. In addition, our results also uncovered the important alterations of nonparenchymal cells, especially macrophages and T/NK populations that responsible for active inflammation responses in alcohol-related hepatitis and immunosuppressive microenvironment in advanced cirrhosis livers, which likely facilitated the malignant progression of ALD. KEY POINTS: This study provides single-cell landscape of human liver samples across different ALD stages. The ALB KRT7 epithelium were enriched in ALD patients, and the function of this epithelial population varied significantly across ALD stages. ALBKRT7 epithelium from advanced alcohol-related cirrhosis had malignant transformation potential and tumour promotion activity. The comprehensive changes of parenchymal and nonparenchymal cells in the ALD livers lay a hidden danger for the further malignant progression.
酒精性肝病（ALD）是一种常见的慢性肝病，由长期过量饮酒引起，在全球所有与肝脏相关的死亡中占比超过一半。与ALD相关的分子机制尚未完全明确。在本研究中，我们对从ALD患者和健康肝脏供体获取的肝脏组织进行了单细胞RNA测序。我们鉴定出一个表达肝细胞和胆管标志物的ALBKRT7上皮细胞群，该细胞群在ALD肝脏中显著扩增。已证实ALBKRT7上皮细胞具有干细胞特性和恶性转化潜能。此外，源自ALBKRT7上皮细胞的ALD类器官通过激活肝癌细胞的Wnt/β-连环蛋白信号通路促进肿瘤生长。最重要的是，阻断Wnt蛋白分泌或敲低Wnt受体可抑制ALD类器官的肿瘤促进作用。我们的研究提供了重要见解，即对于晚期酒精性肝硬化患者，可以靶向Wnt信号通路以预防恶性转化。此外，我们的结果还揭示了非实质细胞的重要变化，特别是巨噬细胞以及T/NK细胞群，它们在酒精性肝炎中引发活跃的炎症反应，并在晚期肝硬化肝脏中形成免疫抑制微环境，这可能促进了ALD的恶性进展。要点：本研究提供了不同ALD阶段人类肝脏样本的单细胞图谱。ALB KRT7上皮细胞在ALD患者中富集，且该上皮细胞群在不同ALD阶段的功能有显著差异。晚期酒精性肝硬化的ALBKRT7上皮细胞具有恶性转化潜能和肿瘤促进活性。ALD肝脏实质细胞和非实质细胞的全面变化为进一步的恶性进展埋下隐患。
