Zhou Miao, Liu Meng, Xue Chao
Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Medical College, Jiaying University, Meizhou 514031, China.
Biology (Basel). 2025 Jun 27;14(7):777. doi: 10.3390/biology14070777.
Liver diseases encompass a wide range of etiologies and involve highly heterogeneous cellular environments, yet the specific cellular states through which genetic risk contributes to disease remain incompletely understood. In this study, we integrated genome-wide association study (GWAS) data from six liver diseases and two metabolic traits with transcriptomic profiles of approximately 168,000 human liver cells at single-cell resolution, using the single-cell disease relevance score (scDRS) approach. Our results revealed that disease-associated genetic signals are predominantly localized to non-parenchymal cells-particularly liver sinusoidal endothelial cells (LSECs), cholangiocytes, and specific subsets of lymphocytes. Notably, we identified marked intra-cell-type heterogeneity, with disease associations confined to specific subpopulations exhibiting immune activation or stress-responsive transcriptional programs. For example, autoimmune and viral liver diseases were linked to immunologically active LSECs and cholangiocytes, whereas their metabolically active counterparts showed no enrichment. These findings highlight the necessity of resolving liver cell complexity to uncover the functional basis of genetic risk and suggest that susceptibility to liver disease is driven by specialized cell states within broader cellular categories. Our study provides a refined cellular map of liver disease susceptibility, offering new perspectives for understanding pathogenic mechanisms and informing targeted therapeutic strategies.
肝脏疾病包含多种病因，涉及高度异质性的细胞环境，但遗传风险导致疾病的具体细胞状态仍未完全明确。在本研究中，我们采用单细胞疾病相关性评分（scDRS）方法，将六种肝脏疾病和两种代谢性状的全基因组关联研究（GWAS）数据与约168,000个人类肝细胞的转录组图谱进行了单细胞分辨率整合。我们的结果显示，与疾病相关的遗传信号主要定位于非实质细胞，特别是肝窦内皮细胞（LSEC）、胆管细胞和特定亚群的淋巴细胞。值得注意的是，我们发现细胞类型内存在显著的异质性，疾病关联仅限于表现出免疫激活或应激反应转录程序的特定亚群。例如，自身免疫性和病毒性肝脏疾病与具有免疫活性的LSEC和胆管细胞有关，而其代谢活跃的对应细胞则未显示富集。这些发现凸显了解析肝细胞复杂性以揭示遗传风险功能基础的必要性，并表明肝脏疾病易感性是由更广泛细胞类别中的特定细胞状态驱动的。我们的研究提供了一份肝脏疾病易感性的精细细胞图谱，为理解致病机制和制定靶向治疗策略提供了新的视角。
